17-74922988-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_173477.5(USH1G):c.85_86insG(p.Asp29GlyfsTer29) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 44 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	UniProt
USH1G	NM_173477.5	c.85_86insG	p.Asp29GlyfsTer29	frameshift_variant	1/3	ENST00000614341.5
USH1G	NM_001282489.3	c.-172_-171insG		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.85_86insG	p.Asp29GlyfsTer29	frameshift_variant	1/3	1	NM_173477.5	P1
OTOP2	ENST00000580223.2	c.-276dup		5_prime_UTR_variant	1/5	1
USH1G	ENST00000579243.1	c.85_86insG	p.Asp29GlyfsTer49	frameshift_variant, NMD_transcript_variant	1/3	2

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

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

Source: dbNSFP v4.3

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;