rs146378222

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_153212.3(GJB4):c.109G>A(p.Val37Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,614,042 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).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

GJB4
NM_153212.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.07

Publications

10 publications found

Variant links:

Genes affected

GJB4 (HGNC:4286): (gap junction protein beta 4) This gene encodes a transmembrane connexin protein that is a component of gap junctions. Mutations in this gene have been associated with erythrokeratodermia variabilis, progressive symmetric erythrokeratoderma and hearing impairment. [provided by RefSeq, Dec 2009]

GJB4 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022521526).

BP6

Variant 1-34761363-G-A is Benign according to our data. Variant chr1-34761363-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225376.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB4	NM_153212.3	MANE Select	c.109G>A	p.Val37Met	missense	Exon 2 of 2	NP_694944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GJB4	ENST00000339480.3	TSL:2 MANE Select	c.109G>A	p.Val37Met	missense	Exon 2 of 2	ENSP00000345868.1
SMIM12	ENST00000426886.1	TSL:1	n.208-42954C>T		intron	N/A	ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	TSL:5	n.*63C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152206

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:

0.00558

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000680

AC:

171

AN:

251388

AF XY:

0.000596

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00636

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000378

AC:

553

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

268

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00589

AC:

234

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000228

AC:

254

AN:

1111854

Other (OTH)

AF:

0.000364

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000361

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00559

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00121

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A

Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

not provided

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.023

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.5

PhyloP100

8.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.82

Sift

Benign

0.12

Sift4G

Benign

0.13

Polyphen

0.99

Vest4

0.84

MVP

0.99

MPC

0.44

ClinPred

0.081

GERP RS

4.6

Varity_R

0.36

gMVP

0.80

Mutation Taster

=27/73

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over