rs111033279

chr11-17531422-A-Gchr11-17531422-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153676.4(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 NM_153676.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.12

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 -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	UniProt
USH1C	NM_153676.4	c.225T>C	p.Asp75=	synonymous_variant	3/27	ENST00000005226.12
USH1C	NM_005709.4	c.225T>C	p.Asp75=	synonymous_variant	3/21	ENST00000318024.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 791 AN: 152114 Hom.: 21 Cov.: 33

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.: 28 AF XY: 0.00699 AC XY: 949 AN XY: 135688

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.: 32 AF XY: 0.00294 AC XY: 2139 AN XY: 727170

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.: 21 Cov.: 33 AF XY: 0.00638 AC XY: 475 AN XY: 74436

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.: 0

Bravo AF: 0.00591

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	Eurofins Ntd Llc (ga)	Jul 23, 2015	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -

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

Other links and lift over

dbSNP: rs111033279; hg19: chr11-17552969;