rs782350886
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000260.4(MYO7A):c.3491G>A(p.Arg1164Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,600,224 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1164W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3491G>A | p.Arg1164Gln | missense_variant | 27/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3491G>A | p.Arg1164Gln | missense_variant | 27/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000134 AC: 3AN: 224160Hom.: 0 AF XY: 0.0000164 AC XY: 2AN XY: 121636
GnomAD4 exome AF: 0.0000131 AC: 19AN: 1448048Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10AN XY: 718980
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74340
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 30, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Usher syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Mar 28, 2024 | The c.3491G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1164 (p.Arg1164Gln). The highest population filtering allele frequency with a confidence interval of 0.95 in gnomAD v4 is 0.00001446 (4/89272 alleles) in the South Asian population, which is lower than the ClinGen Hearing Loss VCEP threshold (<=0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.935, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PP3. (ClinGen Hearing Loss VCEP specifications version 2, 01.17.2024) - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 12, 2017 | - - |
Usher syndrome type 1B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 16, 2021 | - - |
MYO7A-Related Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1164 of the MYO7A protein (p.Arg1164Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MYO7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 229012). 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 MYO7A protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at