rs10832796

chr11-17501091-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_153676.4(USH1C):c.2340C>T(p.Val780=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,060 control chromosomes in the GnomAD database, including 61,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4221 hom., cov: 33)
  • Exomes 𝑓: 0.27 (57112 hom.)
• Consequence: USH1C NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.43

Genes affected

USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 11-17501091-G-A is Benign according to our data. Variant chr11-17501091-G-A is described in ClinVar as [Benign]. Clinvar id is 47997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17501091-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4	c.2340C>T	p.Val780=	synonymous_variant	23/27	ENST00000005226.12
USH1C	NM_005709.4	c.1440C>T	p.Val480=	synonymous_variant	18/21	ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12	c.2340C>T	p.Val780=	synonymous_variant	23/27	5	NM_153676.4
USH1C	ENST00000318024.9	c.1440C>T	p.Val480=	synonymous_variant	18/21	1	NM_005709.4	P1

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32544 AN: 152044 Hom.: 4221 Cov.: 33

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.254 AC: 63640 AN: 250336 Hom.: 8785 AF XY: 0.258 AC XY: 34945 AN XY: 135352

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.268

Gnomad SAS exome AF: 0.194

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.275 AC: 401161 AN: 1460898 Hom.: 57112 Cov.: 40 AF XY: 0.273 AC XY: 198318 AN XY: 726748

Gnomad4 AFR exome AF: 0.0449

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.358

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.214 AC: 32538 AN: 152162 Hom.: 4221 Cov.: 33 AF XY: 0.214 AC XY: 15923 AN XY: 74382

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.351

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.285

Gnomad4 OTH AF: 0.238

Alfa AF: 0.268 Hom.: 3894

Bravo AF: 0.205

Asia WGS AF: 0.206 AC: 715 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1C Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 24, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Autosomal recessive nonsyndromic hearing loss 18A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	2.4
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10832796; hg19: chr11-17522638; COSMIC: COSV50014490; COSMIC: COSV50014490;