rs35983826

Positions:

chr1-34785560-C-T

Variant summary

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

The NM_024009.3(GJB3):c.798C>T(p.Asn266Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 1,613,610 control chromosomes in the GnomAD database, including 7,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.090 ( 666 hom., cov: 32)

Exomes 𝑓: 0.090 ( 6442 hom. )

Consequence

GJB3
NM_024009.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.335

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 1-34785560-C-T is Benign according to our data. Variant chr1-34785560-C-T is described in ClinVar as [Benign]. Clinvar id is 46087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785560-C-T is described in Lovd as [Benign]. Variant chr1-34785560-C-T is described in Lovd as [Likely_benign]. Variant chr1-34785560-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.335 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 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.798C>T	p.Asn266Asn	synonymous_variant	2/2	ENST00000373366.3	NP_076872.1	O75712A0A654ICK0
GJB3	NM_001005752.2 linkuse as main transcript	c.798C>T	p.Asn266Asn	synonymous_variant	2/2		NP_001005752.1	O75712A0A654ICK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJB3	ENST00000373366.3 linkuse as main transcript	c.798C>T	p.Asn266Asn	synonymous_variant	2/2	1	NM_024009.3	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3 linkuse as main transcript	c.798C>T	p.Asn266Asn	synonymous_variant	2/2	1		ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1 linkuse as main transcript	n.208-67151G>A		intron_variant		1		ENSP00000429902.1	E5RH51
ENSG00000255811	ENST00000542839.1 linkuse as main transcript	n.110+2428G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0899

AC:

13673

AN:

152072

Hom.:

666

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0784

Gnomad AMI

AF:

0.0802

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0971

GnomAD3 exomes

AF:

0.0878

AC:

22017

AN:

250664

Hom.:

1178

AF XY:

0.0915

AC XY:

12414

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.0792

Gnomad AMR exome

AF:

0.0515

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.00136

Gnomad SAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.0997

Gnomad OTH exome

AF:

0.0967

GnomAD4 exome

AF:

0.0897

AC:

131121

AN:

1461420

Hom.:

6442

Cov.:

AF XY:

0.0916

AC XY:

66605

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0772

Gnomad4 AMR exome

AF:

0.0540

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.00108

Gnomad4 SAS exome

AF:

0.117

Gnomad4 FIN exome

AF:

0.118

Gnomad4 NFE exome

AF:

0.0908

Gnomad4 OTH exome

AF:

0.0904

GnomAD4 genome

AF:

0.0898

AC:

13674

AN:

152190

Hom.:

666

Cov.:

AF XY:

0.0902

AC XY:

6712

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0782

Gnomad4 AMR

AF:

0.0715

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.111

Gnomad4 FIN

AF:

0.122

Gnomad4 NFE

AF:

0.101

Gnomad4 OTH

AF:

0.0961

Alfa

AF:

0.0967

Hom.:

326

Bravo

AF:

0.0827

Asia WGS

AF:

0.0640

AC:

221

AN:

3478

EpiCase

AF:

0.101

EpiControl

AF:

0.0955

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asn266Asn 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 10.1% (712/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs35983826). -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Erythrokeratodermia variabilis et progressiva 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.63

DANN

Benign

0.77

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