dbSNP rs145247495: GJB3:p.Arg22Ser (chr1-34784826-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_024009.3(GJB3):c.64C>A(p.Arg22Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Publications

0 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: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

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.64C>A	p.Arg22Ser	missense	Exon 2 of 2	NP_076872.1	O75712
	GJB3	NM_001005752.2		c.64C>A	p.Arg22Ser	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.64C>A	p.Arg22Ser	missense	Exon 2 of 2	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3	TSL:1	c.64C>A	p.Arg22Ser	missense	Exon 2 of 2	ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1	TSL:1	n.208-66417G>T		intron	N/A	ENSP00000429902.1	E5RH51

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251396

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

4.9

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.94

MutPred

0.92

Loss of MoRF binding (P = 0.006)

MVP

0.99

MPC

0.42

ClinPred

1.0

GERP RS

5.8

Varity_R

0.94

gMVP

0.90

Mutation Taster

=49/51

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over