17-74922988-T-TC

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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.89
Variant links:
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

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH1GNM_173477.5 linkc.85dupG p.Asp29fs frameshift_variant 1/3 ENST00000614341.5 NP_775748.2
USH1GNM_001282489.3 linkc.-172dupG 5_prime_UTR_variant 1/3 NP_001269418.1 Q495M9B4DL95

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH1GENST00000614341.5 linkc.85dupG p.Asp29fs frameshift_variant 1/31 NM_173477.5 ENSP00000480279.1 Q495M9
OTOP2ENST00000580223 linkc.-276dupC 5_prime_UTR_variant 1/51 ENSP00000463837.2 A0A6E1ZAN8
USH1GENST00000579243.1 linkn.85dupG non_coding_transcript_exon_variant 1/32 ENSP00000462568.1 J3KSN5

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
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 submitterresearchKing Laboratory, University of WashingtonFeb 28, 2023This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-72919083; API