rs139996942

chr11-17509510-C-Achr11-17509510-C-Gchr11-17509510-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_153676.4(USH1C):c.1859G>T(p.Arg620Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 581,820 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts 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. R620C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.039 ( 18 hom., cov: 0)

Exomes 𝑓: 0.0025 ( 25 hom. )

Consequence

USH1C
NM_153676.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.34

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17509511-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.004986495).

BP6

Variant 11-17509510-C-A is Benign according to our data. Variant chr11-17509510-C-A is described in ClinVar as [Benign]. Clinvar id is 166377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17509510-C-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.1859G>T	p.Arg620Leu	missense_variant	18/27	ENST00000005226.12
USH1C	NM_005709.4 linkuse as main transcript	c.1285-7530G>T		intron_variant		ENST00000318024.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.1859G>T	p.Arg620Leu	missense_variant	18/27	5	NM_153676.4		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.1285-7530G>T		intron_variant		1	NM_005709.4	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

1366

AN:

35200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000969

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.0529

GnomAD3 exomes

AF:

0.00276

AC:

631

AN:

228446

Hom.:

AF XY:

0.00210

AC XY:

260

AN XY:

124042

show subpopulations

Gnomad AFR exome

AF:

0.0364

Gnomad AMR exome

AF:

0.00208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.000553

GnomAD4 exome

AF:

0.00254

AC:

1388

AN:

546578

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

592

AN XY:

279170

show subpopulations

Gnomad4 AFR exome

AF:

0.0705

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000303

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000235

Gnomad4 OTH exome

AF:

0.00535

GnomAD4 genome

AF:

0.0389

AC:

1370

AN:

35242

Hom.:

Cov.:

AF XY:

0.0382

AC XY:

642

AN XY:

16810

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000967

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.0519

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.0106

ESP6500AA

AF:

0.0316

AC:

139

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00330

AC:

400

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2017	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)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg620Leu in Exon 18 of USH1C: This variant is not expected to have clinical sig nificance because it has been identified in 2.9% (110/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs139996942). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.030

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.99

REVEL

Benign

0.23

Sift

Uncertain

0.0030

Sift4G

Benign

0.13

Vest4

0.66

MVP

0.58

MPC

0.080

ClinPred

0.016

GERP RS

5.9

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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