rs121908852

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_024009.3(GJB3):c.580G>A(p.Ala194Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0004 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A194D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:5

Conservation

PhyloP100: 4.15

Publications

26 publications found

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:

ENSG00000255811 (HGNC:):

ENSG00000255811 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013227105).

BP6

Variant 1-34785342-G-A is Benign according to our data. Variant chr1-34785342-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6493.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000467 (71/152114) while in subpopulation EAS AF = 0.00641 (33/5150). AF 95% confidence interval is 0.00469. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3 link	c.580G>A	p.Ala194Thr	missense_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1	O75712A0A654ICK0
GJB3	NM_001005752.2 link	c.580G>A	p.Ala194Thr	missense_variant	Exon 2 of 2		NP_001005752.1	O75712A0A654ICK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJB3	ENST00000373366.3 link	c.580G>A	p.Ala194Thr	missense_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3 link	c.580G>A	p.Ala194Thr	missense_variant	Exon 2 of 2	1		ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1 link	n.208-66933C>T		intron_variant	Intron 2 of 4	1		ENSP00000429902.1	E5RH51
ENSG00000255811	ENST00000542839.1 link	n.110+2646C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00639

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000839

AC:

211

AN:

251398

AF XY:

0.000795

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00696

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000393

AC:

574

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

284

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00753

AC:

299

AN:

39700

South Asian (SAS)

AF:

0.000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00178

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000103

AC:

115

AN:

1111930

Other (OTH)

AF:

0.000364

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

138

184

230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000467

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41488

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00641

AC:

AN:

5150

South Asian (SAS)

AF:

0.000624

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68010

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.000306

ExAC

AF:

0.000881

AC:

107

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 30, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15469079, 27057829, 20627047, 33126609, 22617145, 24612839, 31015822, 25788563, 20593197, 31541171, 25724631, 30733538, 30245029, 19050930, 20981092, 25262649, 23638949, 22652773) -

Jul 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675236:Autosomal dominant nonsyndromic hearing loss 2B;C4551486:Erythrokeratodermia variabilis et progressiva 1

Uncertain:1Benign:1

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deafness, digenic, GJB2/GJB3

Pathogenic:1

Feb 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Erythrokeratodermia variabilis et progressiva 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.40

T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

-0.034

MutationAssessor

Benign

1.1

L;L

PhyloP100

4.2

PrimateAI

Benign

0.47

PROVEAN

Benign

1.6

N;N

REVEL

Uncertain

0.56

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.16

B;B

Vest4

0.19

MVP

0.90

MPC

0.39

ClinPred

0.039

GERP RS

4.2

Varity_R

0.18

gMVP

0.76

Mutation Taster

=65/35

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over