rs61732640

Positions:

chr1-34785239-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000373366.3(GJB3):c.477G>A(p.Pro159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,613,878 control chromosomes in the GnomAD database, including 350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 162 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 188 hom. )

Consequence

GJB3
ENST00000373366.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.55

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-34785239-G-A is Benign according to our data. Variant chr1-34785239-G-A is described in ClinVar as [Benign]. Clinvar id is 163530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785239-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3 linkuse as main transcript	c.477G>A	p.Pro159=	synonymous_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2 linkuse as main transcript	c.477G>A	p.Pro159=	synonymous_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GJB3	ENST00000373366.3 linkuse as main transcript	c.477G>A	p.Pro159=	synonymous_variant	2/2	1	NM_024009.3	ENSP00000362464	P1
GJB3	ENST00000373362.3 linkuse as main transcript	c.477G>A	p.Pro159=	synonymous_variant	2/2	1		ENSP00000362460	P1
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-66830C>T		intron_variant, NMD_transcript_variant		1		ENSP00000429902
	ENST00000542839.1 linkuse as main transcript	n.110+2749C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3940

AN:

152026

Hom.:

161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0880

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00976

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0234

GnomAD3 exomes

AF:

0.00794

AC:

1995

AN:

251370

Hom.:

AF XY:

0.00598

AC XY:

813

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0943

Gnomad AMR exome

AF:

0.00480

Gnomad ASJ exome

AF:

0.0173

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000545

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00326

AC:

4758

AN:

1461734

Hom.:

188

Cov.:

AF XY:

0.00289

AC XY:

2099

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.0937

Gnomad4 AMR exome

AF:

0.00512

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000869

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000275

Gnomad4 OTH exome

AF:

0.00828

GnomAD4 genome

AF:

0.0259

AC:

3946

AN:

152144

Hom.:

162

Cov.:

AF XY:

0.0254

AC XY:

1888

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0879

Gnomad4 AMR

AF:

0.00975

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.0296

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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 28, 2023	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2015	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro159Pro in Exon 02 of GJB3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 8.8% (328/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61732640). -

Erythrokeratodermia variabilis et progressiva 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.032

DANN

Benign

0.78

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