rs146378222

Positions:

chr1-34761363-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 id is 225376.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000361 (55/152324) while in subpopulation EAS AF= 0.00559 (29/5184). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB4	NM_153212.3 linkuse as main transcript	c.109G>A	p.Val37Met	missense_variant	2/2	ENST00000339480.3	NP_694944.1
GJB4	XM_011540679.3 linkuse as main transcript	c.109G>A	p.Val37Met	missense_variant	2/2		XP_011538981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB4	ENST00000339480.3 linkuse as main transcript	c.109G>A	p.Val37Met	missense_variant	2/2	2	NM_153212.3	ENSP00000345868	P1
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-42954C>T		intron_variant, NMD_transcript_variant		1		ENSP00000429902

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

GnomAD3 exomes

AF:

0.000680

AC:

171

AN:

251388

Hom.:

AF XY:

0.000596

AC XY:

AN XY:

135864

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 SAS exome

AF:

0.000425

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00589

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000361

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00559

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000365

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

Uncertain significance, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

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

MutationTaster

Benign

0.99

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over