17-74922988-T-TC
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_173477.5(USH1G):c.85dupG(p.Asp29fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 31)
Consequence
USH1G
NM_173477.5 frameshift
NM_173477.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.89
Genes affected
USH1G (HGNC:16356): (USH1 protein network component sans) This gene encodes a protein that contains three ankyrin domains, a class I PDZ-binding motif and a sterile alpha motif. The encoded protein interacts with harmonin, which is associated with Usher syndrome type 1C. This protein plays a role in the development and maintenance of the auditory and visual systems and functions in the cohesion of hair bundles formed by inner ear sensory cells. Mutations in this gene are associated with Usher syndrome type 1G (USH1G). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]
OTOP2 (HGNC:19657): (otopetrin 2) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-74922988-T-TC is Pathogenic according to our data. Variant chr17-74922988-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 2445662.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH1G | ENST00000614341.5 | c.85dupG | p.Asp29fs | frameshift_variant | 1/3 | 1 | NM_173477.5 | ENSP00000480279.1 | ||
OTOP2 | ENST00000580223 | c.-276dupC | 5_prime_UTR_variant | 1/5 | 1 | ENSP00000463837.2 | ||||
USH1G | ENST00000579243.1 | n.85dupG | non_coding_transcript_exon_variant | 1/3 | 2 | ENSP00000462568.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Usher syndrome type 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Feb 28, 2023 | This variant was found in compound heterozygosity with an USH1G frameshift variant in a patient with Usher Syndrome Type 1, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s family has no other history of hearing loss. This is a single base pair duplication that leads to frameshift which is predicted to lead to a premature stop at codon 57 of the 461-amino acid protein. As of January 2023, this variant has not been reported to ClinVar and is not found on gnomAD. Based on the prediction that this variant leads to a truncated protein, compound heterozygosity with a loss-of-function variant, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
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
Publications
No publications associated with this variant yet.