dbSNP rs61732307: GJB3:p.Tyr189Tyr (chr1-34785329-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.40

Publications

1 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 -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 VariationId is 178609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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.567C>T	p.Tyr189Tyr	synonymous	Exon 2 of 2	NP_076872.1	O75712
	GJB3	NM_001005752.2		c.567C>T	p.Tyr189Tyr	synonymous	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.567C>T	p.Tyr189Tyr	synonymous	Exon 2 of 2	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3	TSL:1	c.567C>T	p.Tyr189Tyr	synonymous	Exon 2 of 2	ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1	TSL:1	n.208-66920G>A		intron	N/A	ENSP00000429902.1	E5RH51

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3127

AN:

152190

Hom.:

101

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00632

AC:

1588

AN:

251390

AF XY:

0.00476

show subpopulations

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 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.:

AF XY:

0.00228

AC XY:

1660

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.0723

AC:

2421

AN:

33468

American (AMR)

AF:

0.00458

AC:

205

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

482

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000239

AC:

266

AN:

1111976

Other (OTH)

AF:

0.00664

AC:

401

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

224

448

671

895

1119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0206

AC:

3130

AN:

152308

Hom.:

102

Cov.:

AF XY:

0.0202

AC XY:

1502

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0695

AC:

2887

AN:

41566

American (AMR)

AF:

0.00745

AC:

114

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68024

Other (OTH)

AF:

0.0180

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00956

Hom.:

Bravo

AF:

0.0234

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

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

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.1

(source)

DANN

Benign

0.79

PhyloP100

1.4

Mutation Taster

=92/8

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