rs35983826

chr1-34785560-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024009.3(GJB3):c.798C>T(p.Asn266=) 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:6
• Conservation: PhyloP100: -0.335

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]

(HGNC:):

ACMG classification

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	UniProt
GJB3	NM_024009.3	c.798C>T	p.Asn266=	synonymous_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.798C>T	p.Asn266=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.798C>T	p.Asn266=	synonymous_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.798C>T	p.Asn266=	synonymous_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-67151G>A		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2428G>A		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0878 AC: 22017 AN: 250664 Hom.: 1178 AF XY: 0.0915 AC XY: 12414 AN XY: 135654

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

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.: 32 AF XY: 0.0902 AC XY: 6712 AN XY: 74402

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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

Other links and lift over

dbSNP: rs35983826; hg19: chr1-35251161;