rs201314683

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBS2_Supporting

The NM_024009.3(GJB3):c.293G>A(p.Arg98His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 8.09

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain Gap junction beta-3 protein (size 269) in uniprot entity CXB3_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_024009.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.846

BS2

High AC in GnomAd4 at 8 AD,Digenic gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3 linkuse as main transcript	c.293G>A	p.Arg98His	missense_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2 linkuse as main transcript	c.293G>A	p.Arg98His	missense_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GJB3	ENST00000373366.3 linkuse as main transcript	c.293G>A	p.Arg98His	missense_variant	2/2	1	NM_024009.3	ENSP00000362464	P1
GJB3	ENST00000373362.3 linkuse as main transcript	c.293G>A	p.Arg98His	missense_variant	2/2	1		ENSP00000362460	P1
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-66646C>T		intron_variant, NMD_transcript_variant		1		ENSP00000429902
	ENST00000542839.1 linkuse as main transcript	n.110+2933C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251114

Hom.:

AF XY:

0.0000884

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the GJB3 protein (p.Arg98His). This variant is present in population databases (rs201314683, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant erythrokeratodermia variabilis (PMID: 35677558). ClinVar contains an entry for this variant (Variation ID: 179376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 06, 2015

The p.Arg98His variant in GJB3 has been previously identified by our laboratory in 1 Hispanic individual with hearing loss. This variant has also been identifie d in 8/67672 of European chromosomes and 1/11600 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201314683 ). Computational prediction tools and conservation analysis do not provide stron g support for or against an impact to the protein. In summary, the clinical sign ificance of the p.Arg98His variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2022

The c.293G>A (p.R98H) alteration is located in exon 2 (coding exon 1) of the GJB3 gene. This alteration results from a G to A substitution at nucleotide position 293, causing the arginine (R) at amino acid position 98 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Erythrokeratodermia variabilis et progressiva 1

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.69

.;T

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

0.99

D;D

Vest4

0.72

MutPred

0.64

Gain of helix (P = 0.2059);Gain of helix (P = 0.2059);

MVP

1.0

MPC

0.44

ClinPred

0.76

GERP RS

5.8

Varity_R

0.67

gMVP

0.84

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