rs727504890

Variant names:

• chr17-74920229-G-A
• NM_173477.5:c.607C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-74920229-G-A
• chr17-74920229-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_173477.5(USH1G):​c.607C>T​(p.Gln203*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH1G NM_173477.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.00

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 Likely_pathogenic. Variant got 8 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-74920229-G-A is Pathogenic according to our data. Variant chr17-74920229-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2429315.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1G	NM_173477.5	c.607C>T	p.Gln203*	stop_gained	Exon 2 of 3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.298C>T	p.Gln100*	stop_gained	Exon 2 of 3		NP_001269418.1
USH1G	XM_011524296.2	c.298C>T	p.Gln100*	stop_gained	Exon 2 of 3		XP_011522598.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.607C>T	p.Gln203*	stop_gained	Exon 2 of 3	1	NM_173477.5	ENSP00000480279.1
USH1G	ENST00000579243.1	n.*206C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2		ENSP00000462568.1
USH1G	ENST00000579243.1	n.*206C>T		3_prime_UTR_variant	Exon 2 of 3	2		ENSP00000462568.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome Pathogenic:1

Jan 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH1G c.607C>T (p.Gln203X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic within ClinVar (e.g. c.1004dup [p.Leu336fs], c.1311del [p.Lys438fs]). The variant was absent in 240550 control chromosomes (gnomAD). To our knowledge, no occurrence of c.607C>T in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.92
GERP RS		3.5

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: chr17-72916324;