chr11-77204129-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000260.4(MYO7A):c.5380G>A(p.Glu1794Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000594 in 1,599,400 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000061 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 missense
NM_000260.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 9.47
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain MyTH4 2 (size 149) in uniprot entity MYO7A_HUMAN there are 15 pathogenic changes around while only 5 benign (75%) in NM_000260.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYO7A | NM_000260.4 | c.5380G>A | p.Glu1794Lys | missense_variant | 39/49 | ENST00000409709.9 | NP_000251.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYO7A | ENST00000409709.9 | c.5380G>A | p.Glu1794Lys | missense_variant | 39/49 | 1 | NM_000260.4 | ENSP00000386331.3 | ||
| MYO7A | ENST00000458637.6 | c.5266G>A | p.Glu1756Lys | missense_variant | 39/49 | 1 | ENSP00000392185.2 | |||
| MYO7A | ENST00000409619.6 | c.5233G>A | p.Glu1745Lys | missense_variant | 40/50 | 1 | ENSP00000386635.2 | |||
| MYO7A | ENST00000458169.2 | c.2806G>A | p.Glu936Lys | missense_variant | 19/29 | 1 | ENSP00000417017.2 | |||
| MYO7A | ENST00000670577.1 | n.3206G>A | non_coding_transcript_exon_variant | 22/32 | ENSP00000499323.1 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000895 AC: 20AN: 223510Hom.: 0 AF XY: 0.000108 AC XY: 13AN XY: 120728
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GnomAD4 exome AF: 0.0000608 AC: 88AN: 1447204Hom.: 0 Cov.: 31 AF XY: 0.0000710 AC XY: 51AN XY: 718458
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GnomAD4 genome 0.0000460 AC: 7AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1794 of the MYO7A protein (p.Glu1794Lys). This variant is present in population databases (rs762836180, gnomAD 0.02%). 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: 306194). 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Splice predictors are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge - |
| Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 18, 2018 | The p.Glu1794Lys variant in MYO7A has not been previously reported in in the lit erature, but has been reported in ClinVar (Variation ID 306194). It was also ide ntified in 22/113720 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs762836180). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, the clinical significance of the p.Glu1794Lys variant is uncertain. ACMG/ AMP Criteria applied: none. - |
Autosomal recessive nonsyndromic hearing loss 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Usher syndrome type 1B Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 30, 2020 | - - |
Usher syndrome type 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at