rs747656448
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000260.4(MYO7A):c.6487G>A(p.Gly2163Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.6487G>A | p.Gly2163Ser | missense_variant | Exon 48 of 49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.6367G>A | p.Gly2123Ser | missense_variant | Exon 48 of 49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.6340G>A | p.Gly2114Ser | missense_variant | Exon 49 of 50 | 1 | ENSP00000386635.2 | |||
MYO7A | ENST00000458169.2 | c.3913G>A | p.Gly1305Ser | missense_variant | Exon 28 of 29 | 1 | ENSP00000417017.2 | |||
MYO7A | ENST00000670577.1 | n.*1059G>A | non_coding_transcript_exon_variant | Exon 31 of 32 | ENSP00000499323.1 | |||||
MYO7A | ENST00000670577.1 | n.*1059G>A | 3_prime_UTR_variant | Exon 31 of 32 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249272Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135226
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461696Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 8AN XY: 727128
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:4
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.77). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000402267). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
severe-profound -
MYO7A c.6487G>A, p.G2163S alters a highly conserved residue of MYO7A. The variant is homozygous in 12 Palestinian children from 6 different families with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and present in 7/280682 alleles on gnomAD, all heterozygotes. -
not provided Pathogenic:2
Published functional studies demonstrate the p.(G2163S) variant disrupts MYO7A binding to adaptor protein harmonin, which impacts mechanotransduction of cadherin linkages between stererocilia and microvilli (PMID: 28660889); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27460420, 19375528, 12786748, 24105371, 23770805, 26561413, 19888295, 21117948, 28451532, 23226338, 26226137, 30531642, 32747562, 31964843, 38711914, 38465142, 33528536, 10094549, 28660889) -
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2163 of the MYO7A protein (p.Gly2163Ser). This variant is present in population databases (rs747656448, gnomAD 0.005%). This missense change has been observed in individual(s) with autosomal recessive MYO7A-related conditions (PMID: 10094549, 19375528, 19888295, 23770805, 26226137, 28451532). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 402267). 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 not expected to disrupt MYO7A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Usher syndrome Pathogenic:1
Variant summary: MYO7A c.6487G>A (p.Gly2163Ser) results in a non-conservative amino acid change located in the FERM domain (IPR000299) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249272 control chromosomes. c.6487G>A has been reported in the literature in multiple individuals affected with autosomal recessive non-syndromic hearing loss with evidence of familial segregation including in numerous homozygotes (examples: Shazad_2013, AbuRayyan_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32747562, 23770805). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
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Retinal dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at