rs119103281
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001145809.2(MYH14):c.359C>T(p.Ser120Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. S120S) has been classified as Likely benign.
Frequency
Consequence
NM_001145809.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH14 | NM_001145809.2 | c.359C>T | p.Ser120Leu | missense_variant | 2/43 | ENST00000642316.2 | |
MYH14 | NM_001077186.2 | c.359C>T | p.Ser120Leu | missense_variant | 2/42 | ||
MYH14 | NM_024729.4 | c.359C>T | p.Ser120Leu | missense_variant | 2/41 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH14 | ENST00000642316.2 | c.359C>T | p.Ser120Leu | missense_variant | 2/43 | NM_001145809.2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1426832Hom.: 0 Cov.: 33 AF XY: 0.00000283 AC XY: 2AN XY: 706970
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2017 | The S120L variant in the MYH14 gene has been reported to segregate with hearing loss in all affected members of a large German kindred (Yang et al., 2005). The S120L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S120L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S120L as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 120 of the MYH14 protein (p.Ser120Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with deafness (PMID: 16222661, 20533261). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2200). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH14 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal dominant nonsyndromic hearing loss 4A Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2005 | - - |
MYH14-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 07, 2023 | The MYH14 c.359C>T variant is predicted to result in the amino acid substitution p.Ser120Leu. This variant was reported to segregate with hearing loss in 10 affected and 14 unaffected individuals across 4 generations in a single family, although information on which individuals were tested for the variant was not provided (Yang et al. 2005. PubMed ID: 16222661). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at