1-34785119-C-T

Position:

• chr1-34785119-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.357C>T​(p.Asn119=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,614,062 control chromosomes in the GnomAD database, including 3,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (467 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3220 hom.)
• Consequence: GJB3 NM_024009.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.03

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=-0.76).
• BP6: Variant 1-34785119-C-T is Benign according to our data. Variant chr1-34785119-C-T is described in ClinVar as [Benign]. Clinvar id is 46084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785119-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3	c.357C>T	p.Asn119=	synonymous_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.357C>T	p.Asn119=	synonymous_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.357C>T	p.Asn119=	synonymous_variant	2/2	1	NM_024009.3	ENSP00000362464	P1
GJB3	ENST00000373362.3	c.357C>T	p.Asn119=	synonymous_variant	2/2	1		ENSP00000362460	P1
SMIM12	ENST00000426886.1	c.208-66710G>A		intron_variant, NMD_transcript_variant		1		ENSP00000429902
	ENST00000542839.1	n.110+2869G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0701 AC: 10661 AN: 152118 Hom.: 464 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0442

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0594

GnomAD3 exomes AF: 0.0739 AC: 18506 AN: 250572 Hom.: 927 AF XY: 0.0751 AC XY: 10167 AN XY: 135420

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.0544

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.0721

Gnomad NFE exome AF: 0.0531

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0601 AC: 87784 AN: 1461826 Hom.: 3220 Cov.: 34 AF XY: 0.0621 AC XY: 45163 AN XY: 727218

Gnomad4 AFR exome AF: 0.105

Gnomad4 AMR exome AF: 0.0589

Gnomad4 ASJ exome AF: 0.0538

Gnomad4 EAS exome AF: 0.0899

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.0515

Gnomad4 OTH exome AF: 0.0648

GnomAD4 genome AF: 0.0701 AC: 10673 AN: 152236 Hom.: 467 Cov.: 32 AF XY: 0.0716 AC XY: 5328 AN XY: 74438

Gnomad4 AFR AF: 0.0987

Gnomad4 AMR AF: 0.0444

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.0725

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0592

Alfa AF: 0.0500 Hom.: 132

Bravo AF: 0.0684

Asia WGS AF: 0.110 AC: 381 AN: 3478

EpiCase AF: 0.0511

EpiControl AF: 0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Asn119Asn 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 9.9% (370/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs41310442). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

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

Erythrokeratodermia variabilis et progressiva 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Autosomal dominant nonsyndromic hearing loss 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.5
DANN	Benign	0.87

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: rs41310442; hg19: chr1-35250720;