chr1-34784856-C-T

Position:

chr1-34784856-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_024009.3(GJB3):c.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,614,166 control chromosomes in the GnomAD database, including 759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 51 hom., cov: 32)

Exomes 𝑓: 0.030 ( 708 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.13

Variant links:

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

GJB3 links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

ENSG00000255811 (HGNC:):

ENSG00000255811 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_024009.3

BP4

Computational evidence support a benign effect (MetaRNN=0.010469735).

BP6

Variant 1-34784856-C-T is Benign according to our data. Variant chr1-34784856-C-T is described in ClinVar as [Benign]. Clinvar id is 46088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34784856-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3221/152286) while in subpopulation NFE AF= 0.0311 (2117/68024). AF 95% confidence interval is 0.03. There are 51 homozygotes in gnomad4. There are 1605 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3221 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3 link	c.94C>T	p.Arg32Trp	missense_variant	2/2	ENST00000373366.3	NP_076872.1	O75712A0A654ICK0
GJB3	NM_001005752.2 link	c.94C>T	p.Arg32Trp	missense_variant	2/2		NP_001005752.1	O75712A0A654ICK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJB3	ENST00000373366.3 link	c.94C>T	p.Arg32Trp	missense_variant	2/2	1	NM_024009.3	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3 link	c.94C>T	p.Arg32Trp	missense_variant	2/2	1		ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1 link	n.208-66447G>A		intron_variant		1		ENSP00000429902.1	E5RH51
ENSG00000255811	ENST00000542839.1 link	n.110+3132G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3224

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.0547

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0311

Gnomad OTH

AF:

0.0130

GnomAD3 exomes

AF:

0.0234

AC:

5877

AN:

251420

Hom.:

AF XY:

0.0239

AC XY:

3246

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.00734

Gnomad ASJ exome

AF:

0.0149

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0131

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.0326

Gnomad OTH exome

AF:

0.0201

GnomAD4 exome

AF:

0.0297

AC:

43378

AN:

1461880

Hom.:

708

Cov.:

AF XY:

0.0293

AC XY:

21333

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.00818

Gnomad4 ASJ exome

AF:

0.0149

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0128

Gnomad4 FIN exome

AF:

0.0542

Gnomad4 NFE exome

AF:

0.0332

Gnomad4 OTH exome

AF:

0.0248

GnomAD4 genome

AF:

0.0212

AC:

3221

AN:

152286

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1605

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00505

Gnomad4 AMR

AF:

0.0118

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00995

Gnomad4 FIN

AF:

0.0547

Gnomad4 NFE

AF:

0.0311

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0277

Hom.:

109

Bravo

AF:

0.0171

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0368

AC:

142

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0307

AC:

264

ExAC

AF:

0.0242

AC:

2939

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0262

EpiControl

AF:

0.0245

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GJB3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2025	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25262649, 11175305, 12702148, 12165562, 24498627, 20981092, 10757647, 27884173, 10888284, 30245029, 29318123) -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Arg32Trp in Exon 02 of GJB3: This variant is not expected to have clinical signi ficance because it has been identified in 3.0% (211/7020) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs1805063). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Erythrokeratodermia variabilis et progressiva 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

.;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.0

H;H

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.0

D;D

REVEL

Pathogenic

0.68

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.23

MPC

0.40

ClinPred

0.072

GERP RS

5.8

Varity_R

0.83

gMVP

0.96

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