17-74922961-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_173477.5(USH1G):c.111_112del(p.Trp38GlyfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,400,352 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: USH1G NM_173477.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.51

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 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 17-74922961-CAG-C is Pathogenic according to our data. Variant chr17-74922961-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 964294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.111_112del	p.Trp38GlyfsTer19	frameshift_variant	1/3	ENST00000614341.5
USH1G	NM_001282489.3	c.-146_-145del		5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.111_112del	p.Trp38GlyfsTer19	frameshift_variant	1/3	1	NM_173477.5	P1
OTOP2	ENST00000580223.2	c.-299_-298del		5_prime_UTR_variant	1/5	1
USH1G	ENST00000579243.1	c.111_112del	p.Trp38GlyfsTer39	frameshift_variant, NMD_transcript_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000608 AC: 1 AN: 164592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87236

Gnomad AFR exome AF: 0.000106

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000786 AC: 11 AN: 1400352 Hom.: 0 AF XY: 0.00000579 AC XY: 4 AN XY: 690280

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000927

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	USH1G: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 19, 2022	This variant has not been reported in the literature in individuals affected with USH1G-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 964294). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Trp38Glyfs*19) in the USH1G gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH1G are known to be pathogenic (PMID: 12588794, 22219650). -

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

LitVar

Other links and lift over

dbSNP: rs1567941869; hg19: chr17-72919056;