rs369458838
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000260.4(MYO7A):c.3827C>T(p.Ser1276Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,597,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. S1276S) has been classified as Likely benign.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3827C>T | p.Ser1276Leu | missense_variant | 30/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3827C>T | p.Ser1276Leu | missense_variant | 30/49 | 1 | NM_000260.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000181 AC: 4AN: 220990Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 119452
GnomAD4 exome AF: 0.00000346 AC: 5AN: 1445242Hom.: 0 Cov.: 31 AF XY: 0.00000558 AC XY: 4AN XY: 717146
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74284
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 16, 2013 | The Ser1276Leu variant in MYO7A has not been reported in the literature nor iden tified by our laboratory in any other families. However, identification of this variant in trans with another MYO7A in this individual?s daughter who has clinic al features of Usher syndrome increases the likelihood that this variant is path ogenic. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ser1276Leu varian t may impact the protein. It should be noted that this variant has been identifi ed in 1/3582 (0.02%) African American chromosomes from a broad population (NHLBI Exome Sequencing Project; http://evs.gs.washington.edu/EVS), however, its frequ ency is low enough to be consistent with a recessive carrier frequency. In summa ry, this variant is likely to be pathogenic, though additional studies are requi red to fully establish its clinical significance. - |
Usher syndrome Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Jan 24, 2023 | The NM_000260.4:c.3827C>T variant in the MYO7A gene is a missense variant predicted to cause substitution of serine to leucine at amino acid 1276 (p.Ser1276Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0078% (1/12706) in African/African American population ( PM2_Supporting, BS1, and BA1 are not met). This variant has been detected in 1 patient with hearing loss in trans with a likely pathogenic variant (PM3; Partners LMM internal data SCV000204707.4). The computational predictor REVEL gives a score of 0.769, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). In summary, due to limited evidence, this variant is classified as a variant of uncertain significance based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Variant Curation Expert Panel: PM3, PP3. (VCEP specifications version 2.0.0; Dec 21, 2022) - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 19, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1276 of the MYO7A protein (p.Ser1276Leu). This variant is present in population databases (rs369458838, gnomAD 0.008%). 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: 178283). 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. 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