NM_024009.3:c.598G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024009.3(GJB3):c.598G>A(p.Val200Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,613,676 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 163 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 186 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.05

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003349632).

BP6

Variant 1-34785360-G-A is Benign according to our data. Variant chr1-34785360-G-A is described in ClinVar as Benign. ClinVar VariationId is 163535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024009.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	NM_024009.3	MANE Select	c.598G>A	p.Val200Ile	missense	Exon 2 of 2	NP_076872.1	O75712
	GJB3	NM_001005752.2		c.598G>A	p.Val200Ile	missense	Exon 2 of 2	NP_001005752.1	O75712

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB3	ENST00000373366.3	TSL:1 MANE Select	c.598G>A	p.Val200Ile	missense	Exon 2 of 2	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3	TSL:1	c.598G>A	p.Val200Ile	missense	Exon 2 of 2	ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1	TSL:1	n.208-66951C>T		intron	N/A	ENSP00000429902.1	E5RH51

Frequencies

GnomAD3 genomes

AF:

0.0259

AC:

3937

AN:

151736

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00973

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0235

GnomAD2 exomes

AF:

0.00785

AC:

1973

AN:

251422

AF XY:

0.00587

show subpopulations

Gnomad AFR exome

AF:

0.0944

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000580

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00322

AC:

4700

AN:

1461820

Hom.:

186

Cov.:

AF XY:

0.00283

AC XY:

2058

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0936

AC:

3134

AN:

33468

American (AMR)

AF:

0.00510

AC:

228

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

482

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000197

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000284

AC:

316

AN:

1111984

Other (OTH)

AF:

0.00820

AC:

495

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

262

524

785

1047

1309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.0260

AC:

3943

AN:

151856

Hom.:

163

Cov.:

AF XY:

0.0254

AC XY:

1884

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.0881

AC:

3648

AN:

41402

American (AMR)

AF:

0.00971

AC:

148

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5138

South Asian (SAS)

AF:

0.000417

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

67956

Other (OTH)

AF:

0.0232

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

181

362

544

725

906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0102

Hom.:

144

Bravo

AF:

0.0296

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0862

AC:

380

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00965

AC:

1172

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Erythrokeratodermia variabilis et progressiva 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.4

PhyloP100

2.0

PrimateAI

Benign

0.34

PROVEAN

Benign

0.36

REVEL

Benign

0.17

Sift

Benign

0.19

Sift4G

Benign

0.29

Polyphen

0.025

Vest4

0.11

MVP

0.68

MPC

0.074

ClinPred

0.0044

GERP RS

2.1

Varity_R

0.065

gMVP

0.51

Mutation Taster

=97/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over