rs111033279

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153676.4(USH1C):c.225T>C(p.Asp75Asp) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.12

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
autosomal recessive nonsyndromic hearing loss 18A
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

USH1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.225T>C	p.Asp75Asp	synonymous_variant	Exon 3 of 27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.225T>C	p.Asp75Asp	synonymous_variant	Exon 3 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.225T>C	p.Asp75Asp	synonymous_variant	Exon 3 of 27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.225T>C	p.Asp75Asp	synonymous_variant	Exon 3 of 21	1	NM_005709.4	ENSP00000317018.4		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

GnomAD2 exomes

AF:

0.00796

AC:

1998

AN:

250944

AF XY:

0.00699

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 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

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0189

AC:

847

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26134

East Asian (EAS)

AF:

0.0703

AC:

2792

AN:

39690

South Asian (SAS)

AF:

0.000847

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00863

AC:

461

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111950

Other (OTH)

AF:

0.00379

AC:

229

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

296

591

887

1182

1478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00520

AC:

792

AN:

152232

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

475

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41558

American (AMR)

AF:

0.0220

AC:

336

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.0552

AC:

285

AN:

5164

South Asian (SAS)

AF:

0.000416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0118

AC:

125

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68010

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000954

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

Dec 23, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Jul 23, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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

- -

Usher syndrome type 1C

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.8

(source)

DANN

Benign

0.72

PhyloP100

4.1

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over