rs200304238
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000260.4(MYO7A):āc.1403A>Gā(p.His468Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,601,664 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.00019 ( 1 hom. )
Consequence
MYO7A
NM_000260.4 missense
NM_000260.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 7.52
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1403A>G | p.His468Arg | missense_variant | 13/49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.1403A>G | p.His468Arg | missense_variant | 13/49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.1370A>G | p.His457Arg | missense_variant | 14/50 | 1 | ENSP00000386635.2 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000144 AC: 33AN: 229936Hom.: 1 AF XY: 0.000113 AC XY: 14AN XY: 123820
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GnomAD4 exome AF: 0.000186 AC: 269AN: 1449500Hom.: 1 Cov.: 31 AF XY: 0.000161 AC XY: 116AN XY: 719336
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GnomAD4 genome AF: 0.000118 AC: 18AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 30, 2022 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 468 of the MYO7A protein (p.His468Arg). This variant is present in population databases (rs200304238, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 27068579). ClinVar contains an entry for this variant (Variation ID: 553342). 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, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 25, 2022 | Identified with a second MYO7A variant in a patient with prelingual nonsyndromic hearing loss in published literature (Sommen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27068579) - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 16, 2017 | - - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 05, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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