rs587776546

chr17-74920441-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_173477.5(USH1G):c.394_395insG(p.Val132GlyfsTer3) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: USH1G NM_173477.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-74920441-A-AC is Pathogenic according to our data. Variant chr17-74920441-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 2917.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1G	NM_173477.5	c.394_395insG	p.Val132GlyfsTer3	frameshift_variant	2/3	ENST00000614341.5
USH1G	NM_001282489.3	c.85_86insG	p.Val29GlyfsTer3	frameshift_variant	2/3
USH1G	XM_011524296.2	c.85_86insG	p.Val29GlyfsTer3	frameshift_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1G	ENST00000614341.5	c.394_395insG	p.Val132GlyfsTer3	frameshift_variant	2/3	1	NM_173477.5	P1
USH1G	ENST00000579243.1	c.341_342insG	p.Gly115TrpfsTer4	frameshift_variant, NMD_transcript_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Usher syndrome type 1G Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2003

- -

Usher syndrome type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587776546; hg19: chr17-72916536;