11-77130637-G-A
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000479 in 1,461,006 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: 0.0000048 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 start_lost
NM_000260.4 start_lost
Scores
5
7
4
Clinical Significance
Conservation
PhyloP100: 4.05
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000260.4 (MYO7A) was described as [Likely_pathogenic] in ClinVar as 179567
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-77130637-G-A is Pathogenic according to our data. Variant chr11-77130637-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77130637-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.3G>A | p.Met1? | start_lost | 2/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.3G>A | p.Met1? | start_lost | 2/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.3G>A | p.Met1? | start_lost | 2/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.-111G>A | 5_prime_UTR_variant | 2/50 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247242Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134194
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461006Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726664
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GnomAD4 genome ? Cov.: 33
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33
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?
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2017 | - - |
Usher syndrome type 1B Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 16, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | This sequence change affects the initiator methionine of the MYO7A mRNA. The next in-frame methionine is located at codon 12. This variant is present in population databases (rs782787126, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with autosomal recessive Usher syndrome or retinitis pigmentosa (PMID: 30459346; Invitae). ClinVar contains an entry for this variant (Variation ID: 553231). This variant disrupts the p.Gly7 amino acid residue in MYO7A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30303587). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Meniere disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | case-control | Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO) | Dec 14, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;.;N
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Polyphen
B;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0676);Gain of catalytic residue at M1 (P = 0.0676);Gain of catalytic residue at M1 (P = 0.0676);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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