rs121965085
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000260.4(MYO7A):c.1996C>T(p.Arg666Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000124 in 1,612,732 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
MYO7A
NM_000260.4 stop_gained
NM_000260.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.79
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-77174816-C-T is Pathogenic according to our data. Variant chr11-77174816-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77174816-C-T is described in Lovd as [Pathogenic]. Variant chr11-77174816-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYO7A | NM_000260.4 | c.1996C>T | p.Arg666Ter | stop_gained | 17/49 | ENST00000409709.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYO7A | ENST00000409709.9 | c.1996C>T | p.Arg666Ter | stop_gained | 17/49 | 1 | NM_000260.4 | ||
MYO7A | ENST00000458637.6 | c.1996C>T | p.Arg666Ter | stop_gained | 17/49 | 1 | P1 | ||
MYO7A | ENST00000409619.6 | c.1963C>T | p.Arg655Ter | stop_gained | 18/50 | 1 | |||
MYO7A | ENST00000409893.6 | c.61C>T | p.Arg21Ter | stop_gained | 1/11 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000163 AC: 4AN: 246092Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 134046
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460512Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6AN XY: 726434
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31589614, 36240775, 21569298, 33576163, 32531858, 10094549, 27246798, 27957503, 35955564, 35440622, 12786748, 15660226, 15043528, 28075205) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Arg666*) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is present in population databases (rs121965085, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal recessive Usher syndrome (PMID: 10094549, 15660226, 21569298). ClinVar contains an entry for this variant (Variation ID: 11860). For these reasons, this variant has been classified as Pathogenic. - |
Usher syndrome type 1B Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 21, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2005 | - - |
Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 01, 2017 | - - |
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 08, 2021 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 15, 2014 | The p.Arg666X variant in MYO7A has been reported in 4 individuals with Usher syn drome type I, 3 of whom carried a second MYO7A variant (Janecke 1999, Pennings 2 004, Ouyang 2005, Bonnet 2011). This variant has been identified in 4/110570 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs121965085), which is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termina tion codon at position 666, which is predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PVS1, PM2. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A
Vest4
GERP RS
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