rs201046979
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000260.4(MYO7A):c.1606G>A(p.Ala536Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. A536A) has been classified as Likely benign.
Frequency
Consequence
NM_000260.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1606G>A | p.Ala536Thr | missense_variant | 14/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1606G>A | p.Ala536Thr | missense_variant | 14/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1606G>A | p.Ala536Thr | missense_variant | 14/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1573G>A | p.Ala525Thr | missense_variant | 15/50 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151818Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000722 AC: 18AN: 249258Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135222
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461680Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 727128
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151818Hom.: 0 Cov.: 31 AF XY: 0.0000405 AC XY: 3AN XY: 74126
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 536 of the MYO7A protein (p.Ala536Thr). This variant is present in population databases (rs201046979, gnomAD 0.03%). 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: 43154). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 01, 2011 | Ala536Thr in exon 14 of MYO7A: This variant is not expected to have clinical sig nificance because it has been identified by our laboratory in one individual who also carried two pathogenic MYO7A variants. In addition, computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein primarily based upon a lack of conservation across species including mam mals. Of note, opossum, chicken, frog and zebrafish have a threonine (Thr) at th is position despite high nearby amino acid conservation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at