rs201618718
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_016239.4(MYO15A):c.3622C>T(p.Arg1208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,612,292 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1208R) has been classified as Likely benign.
Frequency
Consequence
NM_016239.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO15A | NM_016239.4 | c.3622C>T | p.Arg1208Cys | missense_variant | 3/66 | ENST00000647165.2 | NP_057323.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO15A | ENST00000647165.2 | c.3622C>T | p.Arg1208Cys | missense_variant | 3/66 | NM_016239.4 | ENSP00000495481.1 | |||
MYO15A | ENST00000651088.1 | c.163C>T | p.Arg55Cys | missense_variant | 2/2 | ENSP00000498988.1 | ||||
MYO15A | ENST00000583079.1 | n.5328C>T | non_coding_transcript_exon_variant | 1/1 | 6 |
Frequencies
GnomAD3 genomes AF: 0.000637 AC: 97AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000842 AC: 208AN: 246934Hom.: 0 AF XY: 0.00102 AC XY: 137AN XY: 134284
GnomAD4 exome AF: 0.000863 AC: 1260AN: 1459978Hom.: 2 Cov.: 31 AF XY: 0.000917 AC XY: 666AN XY: 726196
GnomAD4 genome AF: 0.000637 AC: 97AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58AN XY: 74476
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 08, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Nov 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not provided Uncertain:2Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 30, 2022 | BS1_supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2024 | Identified with a second MYO15A variant via carrier screening of parents with two affected children with hearing impairment, as well as Van Maldergem syndrome and co-occurring FAT4 variants (PMID: 37551355); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36703223, 39038432, 37551355) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 11, 2018 | Variant classified as Uncertain Significance - Favor Benign. The p.Arg1208Cys va riant in MYO15A has been previously identified by our laboratory in two individu als with hearing loss; however, a variant in trans was not identied in either of these individuals. This variant has been identified in 0.2% (60/30752) of South Asian chromosomes and 0.1% (132/126234) of European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201618718 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impac t to the protein; however, arginine at position 1208 is not conserved and severa l evolutionarily distant species carry a cysteine, raising the possibility that this change may be tolerated. In summary, while the clinical significance of the p.Arg1208Cys variant is uncertain, its lack of conservation suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at