11-17527316-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_153676.4(USH1C):c.403G>A(p.Val135Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,612,278 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 30)

Exomes 𝑓: 0.0025 ( 5 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 7.57

Variant links:

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]

USH1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011645734).

BP6

Variant 11-17527316-C-T is Benign according to our data. Variant chr11-17527316-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48015.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=2}. Variant chr11-17527316-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00232 (352/151962) while in subpopulation AMR AF= 0.00432 (66/15278). AF 95% confidence interval is 0.00348. There are 3 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.403G>A	p.Val135Ile	missense_variant	Exon 5 of 27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.403G>A	p.Val135Ile	missense_variant	Exon 5 of 21	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.403G>A	p.Val135Ile	missense_variant	Exon 5 of 27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.403G>A	p.Val135Ile	missense_variant	Exon 5 of 21	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

352

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00227

AC:

568

AN:

250276

Hom.:

AF XY:

0.00245

AC XY:

332

AN XY:

135392

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00275

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.00141

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00249

AC:

3634

AN:

1460316

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1821

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.00175

Gnomad4 NFE exome

AF:

0.00283

Gnomad4 OTH exome

AF:

0.00237

GnomAD4 genome

AF:

0.00232

AC:

352

AN:

151962

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

163

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.00432

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000391

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.000378

Gnomad4 NFE

AF:

0.00353

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00281

Hom.:

Bravo

AF:

0.00234

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00303

AC:

ExAC

AF:

0.00227

AC:

275

EpiCase

AF:

0.00294

EpiControl

AF:

0.00450

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Usher syndrome type 1C

Uncertain:1Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Pars Genome Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Sep 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

USH1C: BS2 -

Autosomal recessive nonsyndromic hearing loss 18A

Uncertain:1Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 26, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The USH1C c.403G>A:p.(Val135Ile) heterozygous, possibly deleterious variant was detected in an individual with sloping normal-to-moderate HL. In the same individual, two additional variants, both of them founders, have been detected in two other USH genes; one a known pathogenic variant in PCDH15, c.733C>T:p.(Arg245*), and the other, a VUS in ADGRV1, c.8308T>C:p.(Phe2770Leu), suggesting digenic or trigenic inheritance. -

not specified

Benign:2

Aug 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val135Ile in exon 5 of USH1C: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (227/66532) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145013633). -

Sep 13, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

T;.;.;.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.87

L;.;L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.0

N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.18

T;T;T;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;.;D;.;.

Vest4

0.81

MVP

0.37

MPC

0.36

ClinPred

0.028

GERP RS

5.1

Varity_R

0.29

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over