rs878853236
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000260.4(MYO7A):c.1969C>T(p.Arg657Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,455,778 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: not found (cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 missense
NM_000260.4 missense
Scores
15
2
2
Clinical Significance
Conservation
PhyloP100: -0.0220
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 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969
PP5
Variant 11-77174789-C-T is Pathogenic according to our data. Variant chr11-77174789-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77174789-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1969C>T | p.Arg657Trp | missense_variant | 17/49 | ENST00000409709.9 | NP_000251.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1969C>T | p.Arg657Trp | missense_variant | 17/49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
MYO7A | ENST00000458637.6 | c.1969C>T | p.Arg657Trp | missense_variant | 17/49 | 1 | ENSP00000392185.2 | |||
MYO7A | ENST00000409619.6 | c.1936C>T | p.Arg646Trp | missense_variant | 18/50 | 1 | ENSP00000386635.2 | |||
MYO7A | ENST00000409893.6 | c.34C>T | p.Arg12Trp | missense_variant | 1/11 | 5 | ENSP00000386689.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000420 AC: 1AN: 238114Hom.: 0 AF XY: 0.00000772 AC XY: 1AN XY: 129566
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GnomAD4 exome AF: 0.00000550 AC: 8AN: 1455778Hom.: 0 Cov.: 34 AF XY: 0.00000553 AC XY: 4AN XY: 723550
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GnomAD4 genome Cov.: 33
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33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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: 16963483, 24105371, 36164746, 26309859, 33576794, 34148116, 33671976, 36460718, 26338283, 27460420) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 657 of the MYO7A protein (p.Arg657Trp). 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 missense change has been observed in individuals with autosomal recessive non-syndromic deafness or Usher syndrome (PMID: 24105371, 26309859, 26338283, 27460420). ClinVar contains an entry for this variant (Variation ID: 242392). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | May 07, 2018 | Recessive, congenital, profound NSHL - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 02, 2018 | - - |
Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D;.
Sift4G
Pathogenic
D;D;D;D;.
Polyphen
D;.;.;.;.
Vest4
MutPred
Loss of catalytic residue at R657 (P = 0.0645);Loss of catalytic residue at R657 (P = 0.0645);Loss of catalytic residue at R657 (P = 0.0645);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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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