Example 1: Disease mutation CHRND_L63P

This single base exchange in the CHRND gene is listed in NCBI ClinVar as a known disease-causing variant (dbSNP:rs121909508) for MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL, OMIM 100720#0013).

It results in an amino acid exchange from leucin to proline. The involved amino acid residue is part of a functional domain (topo domain) and is highly conserved (amino acids identical in all homologes). As a consequence of the mutation, the topo domain is lost. The phyloP and phastCons values for the changed nucleotide are very high, again indicating strong evolutionary conservation.

The mutation is identical to the one in example 2 but this time, the query is submitted via the MutationTaster Chromosomal Position interface. The analysis is therefore conducted for all available transcripts at the respective position and not just for a single transcript.

Example 2: Disease mutation CHRND_L63P

This single base exchange in the CHRND gene is listed in NCBI ClinVar as a known disease-causing variant (dbSNP:rs121909508) for MYASTHENIC SYNDROME, CONGENITAL, FAST-CHANNEL, OMIM 100720#0013).

It results in an amino acid exchange from leucin to proline. The involved amino acid residue is part of a functional domain (topo domain) and is highly conserved (amino acids identical in all homologes). As a consequence of the mutation, the topo domain is lost. The phyloP and phastCons values for the changed nucleotide are very high, again indicating strong evolutionary conservation.

The mutation is identical to the one in example 1 but this time, the query is submitted via the MutationTaster Specific Transcript interface. The analysis is therefore conducted only for a single transcript (ENST00000258385) and not for all available transcripts at the respective position.

Example 3: Polymorphism AGRN_g.28670_28671delAG

This example is a deletion that was found more than 4 times in the 1000Genomes Project (TGP) in homozygous state. There is no amino acid exchange since the deletion lies within an intronic sequence. As it can be seen from the low phyloP / phastCons values, the deleted bases are hardly conserved. The splice site changes should be interpreted with care, especially in this context where the variant is not conserved and has been frequently found homozygous in the TGP. It can be assumed that the splice site changes are false positive predictions. The classification 'benign' is due to the findings in the TGP but the high probability indicates, that MutationTaster would have classified this variant as non-disease causing anyway.

Example 4: Disease mutation CLDN16_G191R

This alteration is a single base exchange that is listed in NCBI ClinVar as a known disease-causing variant (dbSNP:rs104893721) for HOMG3 (HYPOMAGNESEMIA 3, OMIM 603959#0003).

The altered base leads to an amino acid substitution at a highly conserved residue (amino acid is identical in all homologs). Since the amino acid exchange is quite dramatic (a neutral glycine is replaced with a charged arginine), the substitution has a high amino acid exchange score (3.41, extracted from the Grantham matrix).

As reflected by the high phyloP and phastCons scores, the position is also conserved on the DNA level. The predicted splice site changes are only marginal and can therefore be neglected. The classification 'disease causing' is due to the ClinVar entry but the high probability indicates, that MutationTaster would have classified this variant as deleterious anyway.

Example 5: Disease mutation SOD1_H47R

This example is a mutation that is listed in NCBI ClinVar as a known disease-causing variant (dbSNP:rs121912443) for ALS (AMYOTROPHIC LATERAL SCLEROSIS 1, OMIM 147450#0008). The involved amino acid residue is highly conserved and lies within the catalytic copper-binding site of the protein, which is displayed as lost protein feature.

The phyloP and phastCons values for this position (4.283 and 0.996) are also very high, indicating strong evolutionary conservation. Again, the prediction is due to the ClinVar entry but has a very high probability anyway.

Example 6: Tiny sample VCF file

The VCF file TinyExample.vcf only contains three lines to illustrate the file format:

3	190122694	.	G	A	116	.	.	GT:DP	0/1:154
1	984171	.	CAG	C	116	.	.	GT:DP	0/1:154
21	33036170	.	A	G	116	.	.	GT:DP	0/1:154

Example 7: Sample exome (cystic fibrosis)

The zipped file SampleExome_CF.vcf.gz contains a public VCF file with disease mutations in the CFTR gene spiked in. It is good practice to zip or gzip large VCF files before upload to MutationTaster. All variants must be in VCF format and refer to GRCh37 / hg19.