rs104894652

Positions:

• chr17-74922961-C-T

Variant summary

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

The NM_173477.5(USH1G):​c.113G>A​(p.Trp38Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000107 in 1,400,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: USH1G NM_173477.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.07

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 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-C-T is Pathogenic according to our data. Variant chr17-74922961-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2918.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-74922961-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1G	NM_173477.5	c.113G>A	p.Trp38Ter	stop_gained	1/3	ENST00000614341.5	NP_775748.2
USH1G	NM_001282489.3	c.-144G>A		5_prime_UTR_variant	1/3		NP_001269418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1G	ENST00000614341.5	c.113G>A	p.Trp38Ter	stop_gained	1/3	1	NM_173477.5	ENSP00000480279	P1
OTOP2	ENST00000580223.2	c.-304C>T		5_prime_UTR_variant	1/5	1		ENSP00000463837
USH1G	ENST00000579243.1	c.113G>A	p.Trp38Ter	stop_gained, NMD_transcript_variant	1/3	2		ENSP00000462568

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1400352 Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 7 AN XY: 690280

Gnomad4 AFR exome AF: 0.00

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: 0.0000139

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Usher syndrome type 1G Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2021

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Usher syndrome (PMID: 15660226). ClinVar contains an entry for this variant (Variation ID: 2918). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp38*) 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.80
GERP RS		4.1

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: rs104894652; hg19: chr17-72919056;