rs35983826

Variant names:

• chr1-34785560-C-T
• rs35983826
• NM_024009.3:c.798C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.335
• Publications: 13 publications found

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]

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

ENSG00000255811 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 46087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GJB3	NM_024009.3	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.798C>T	p.Asn266Asn	synonymous_variant	Exon 2 of 2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-67151G>A		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2428G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0899 AC: 13673 AN: 152072 Hom.: 666 Cov.: 32

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

GnomAD2 exomes AF: 0.0878 AC: 22017 AN: 250664 AF XY: 0.0915

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 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.: 34 AF XY: 0.0916 AC XY: 66605 AN XY: 727030

African (AFR) AF: 0.0772 AC: 2585 AN: 33472

American (AMR) AF: 0.0540 AC: 2415 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2650 AN: 26134

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39700

South Asian (SAS) AF: 0.117 AC: 10074 AN: 86236

European-Finnish (FIN) AF: 0.118 AC: 6317 AN: 53398

Middle Eastern (MID) AF: 0.112 AC: 645 AN: 5750

European-Non Finnish (NFE) AF: 0.0908 AC: 100936 AN: 1111646

Other (OTH) AF: 0.0904 AC: 5456 AN: 60362

GnomAD4 genome AF: 0.0898 AC: 13674 AN: 152190 Hom.: 666 Cov.: 32 AF XY: 0.0902 AC XY: 6712 AN XY: 74402

African (AFR) AF: 0.0782 AC: 3247 AN: 41544

American (AMR) AF: 0.0715 AC: 1094 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.111 AC: 535 AN: 4820

European-Finnish (FIN) AF: 0.122 AC: 1293 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6840 AN: 68004

Other (OTH) AF: 0.0961 AC: 203 AN: 2112

Alfa AF: 0.0983 Hom.: 450

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

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Apr 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Erythrokeratodermia variabilis et progressiva 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35983826; hg19: chr1-35251161; COSMIC: COSV108219568;