dbSNP rs145436095: GJB3:p.His124Gln (chr1-34785134-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024009.3(GJB3):c.372C>G(p.His124Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H124R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.314

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3 link	c.372C>G	p.His124Gln	missense_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2 link	c.372C>G	p.His124Gln	missense_variant	Exon 2 of 2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GJB3	ENST00000373366.3 link	c.372C>G	p.His124Gln	missense_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3 link	c.372C>G	p.His124Gln	missense_variant	Exon 2 of 2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1 link	n.208-66725G>C		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1 link	n.110+2854G>C		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

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:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.42

T;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.27

.;T

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

-0.31

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.54

Sift

Benign

0.082

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.47

P;P

Vest4

0.60

MutPred

0.35

Loss of ubiquitination at K123 (P = 0.1016);Loss of ubiquitination at K123 (P = 0.1016);

MVP

0.92

MPC

0.40

ClinPred

0.88

GERP RS

2.5

Varity_R

0.21

gMVP

0.87

Mutation Taster

=47/53

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over