chr11-17531422-A-G

Position:

chr11-17531422-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000318024.9(USH1C):c.225T>C(p.Asp75=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00326 in 1,613,964 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 21 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 119 hom. )

Consequence

USH1C
ENST00000318024.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.12

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 11-17531422-A-G is Benign according to our data. Variant chr11-17531422-A-G is described in ClinVar as [Benign]. Clinvar id is 47996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.225T>C	p.Asp75=	synonymous_variant	3/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4 linkuse as main transcript	c.225T>C	p.Asp75=	synonymous_variant	3/21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.225T>C	p.Asp75=	synonymous_variant	3/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.225T>C	p.Asp75=	synonymous_variant	3/21	1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

791

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.0547

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0118

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00796

AC:

1998

AN:

250944

Hom.:

AF XY:

0.00699

AC XY:

949

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0581

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.00977

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00539

GnomAD4 exome

AF:

0.00306

AC:

4470

AN:

1461732

Hom.:

119

Cov.:

AF XY:

0.00294

AC XY:

2139

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0189

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0703

Gnomad4 SAS exome

AF:

0.000847

Gnomad4 FIN exome

AF:

0.00863

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152232

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

475

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.0552

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.0118

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000461

Hom.:

Bravo

AF:

0.00591

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 23, 2010	Asp75Asp in exon 3 of USH1C: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located near a s plice junction and was identified in 5/120 (4.2%) of Black individuals (rs111033 279). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1C

Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.8

DANN

Benign

0.72

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

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