rs61732307

Variant names:

• chr1-34785329-C-T
• rs61732307
• NM_024009.3:c.567C>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.567C>T​(p.Tyr189Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,004 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (118 hom.)
• Consequence: GJB3 NM_024009.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.40

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-34785329-C-T is Benign according to our data. Variant chr1-34785329-C-T is described in ClinVar as [Benign]. Clinvar id is 178609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785329-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3	c.567C>T	p.Tyr189Tyr	synonymous_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.567C>T	p.Tyr189Tyr	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.567C>T	p.Tyr189Tyr	synonymous_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.567C>T	p.Tyr189Tyr	synonymous_variant	Exon 2 of 2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-66920G>A		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2659G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3127 AN: 152190 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00632 AC: 1588 AN: 251390 Hom.: 44 AF XY: 0.00476 AC XY: 646 AN XY: 135856

Gnomad AFR exome AF: 0.0724

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000519

Gnomad OTH exome AF: 0.00472

GnomAD4 exome AF: 0.00260 AC: 3799 AN: 1461696 Hom.: 118 Cov.: 33 AF XY: 0.00228 AC XY: 1660 AN XY: 727148

Gnomad4 AFR exome AF: 0.0723

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.0206 AC: 3130 AN: 152308 Hom.: 102 Cov.: 32 AF XY: 0.0202 AC XY: 1502 AN XY: 74480

Gnomad4 AFR AF: 0.0695

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00934 Hom.: 21

Bravo AF: 0.0234

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Dec 07, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Tyr189Tyr 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 6.6% (245/3738) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs61732307). -

Aug 26, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Erythrokeratodermia variabilis et progressiva 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.61
CADD	Benign	8.1
DANN	Benign	0.79

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: rs61732307; hg19: chr1-35250930;