11-17517424-C-T

Variant names:

Variant summary

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

The NM_005709.4(USH1C):c.1261G>A(p.Gly421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,593,664 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G421D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 66 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 71 hom. )

Consequence

USH1C
NM_005709.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.14

Publications

4 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 (MetaRNN=0.0026290119).

BP6

Variant 11-17517424-C-T is Benign according to our data. Variant chr11-17517424-C-T is described in ClinVar as Benign. ClinVar VariationId is 45426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_005709.4 link	c.1261G>A	p.Gly421Ser	missense_variant	Exon 15 of 21	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9
USH1C	NM_153676.4 link	c.1211-1134G>A		intron_variant	Intron 14 of 26	ENST00000005226.12	NP_710142.1	Q9Y6N9-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000318024.9 link	c.1261G>A	p.Gly421Ser	missense_variant	Exon 15 of 21	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1
USH1C	ENST00000005226.12 link	c.1211-1134G>A		intron_variant	Intron 14 of 26	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2225

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00397

AC:

869

AN:

219106

AF XY:

0.00318

show subpopulations

Gnomad AFR exome

AF:

0.0500

Gnomad AMR exome

AF:

0.00328

Gnomad ASJ exome

AF:

0.00287

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.00449

GnomAD4 exome

AF:

0.00184

AC:

2654

AN:

1441374

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1177

AN XY:

714746

show subpopulations

African (AFR)

AF:

0.0539

AC:

1788

AN:

33148

American (AMR)

AF:

0.00374

AC:

158

AN:

42280

Ashkenazi Jewish (ASJ)

AF:

0.00303

AC:

AN:

25710

East Asian (EAS)

AF:

0.00

AC:

AN:

38924

South Asian (SAS)

AF:

0.000121

AC:

AN:

82670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51872

Middle Eastern (MID)

AF:

0.00421

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.000310

AC:

342

AN:

1101466

Other (OTH)

AF:

0.00426

AC:

254

AN:

59606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

155

311

466

622

777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.0147

AC:

2232

AN:

152290

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

1095

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0494

AC:

2054

AN:

41556

American (AMR)

AF:

0.00752

AC:

115

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68020

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

197

295

394

492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00689

Hom.:

Bravo

AF:

0.0168

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0423

AC:

186

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.00434

AC:

526

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 01, 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. -

May 14, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gly421Ser in Exon 15B of USH1C: This variant is not expected to have clinical si gnificance because it has been identified in 4.3% (162/3734) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs115931035). -

Feb 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

Athena Diagnostics

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

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.045

T;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0026

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;.

PhyloP100

1.1

PROVEAN

Benign

0.75

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.90

T;T;T

Sift4G

Benign

0.47

T;T;T

Polyphen

0.0050

B;.;B

Vest4

0.14

MVP

0.18

ClinPred

0.0016

GERP RS

3.6

Varity_R

0.031

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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