rs747656448
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The ENST00000409709.9(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
Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
MYO7A
ENST00000409709.9 missense
ENST00000409709.9 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.73
Genes affected
MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837
PP5
Variant 11-77213908-G-A is Pathogenic according to our data. Variant chr11-77213908-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.6487G>A | p.Gly2163Ser | missense_variant | 48/49 | ENST00000409709.9 | NP_000251.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.6487G>A | p.Gly2163Ser | missense_variant | 48/49 | 1 | NM_000260.4 | ENSP00000386331 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249272Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135226
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461696Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 8AN XY: 727128
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152242Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74374
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 12, 2017 | - - |
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | severe-profound - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | 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. - |
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 20, 2023 | 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2024 | 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) - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 02, 2023 | 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. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;T;D
Polyphen
D;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0478);.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at