chr1-34785075-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_024009.3(GJB3):c.313C>A(p.His105Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,614,088 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GJB3
NM_024009.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.876

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_024009.3

BP4

Computational evidence support a benign effect (MetaRNN=0.008862764).

BP6

Variant 1-34785075-C-A is Benign according to our data. Variant chr1-34785075-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00212 (323/152286) while in subpopulation AFR AF = 0.00717 (298/41560). AF 95% confidence interval is 0.0065. There are 3 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3 link	c.313C>A	p.His105Asn	missense_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1	O75712A0A654ICK0
GJB3	NM_001005752.2 link	c.313C>A	p.His105Asn	missense_variant	Exon 2 of 2		NP_001005752.1	O75712A0A654ICK0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJB3	ENST00000373366.3 link	c.313C>A	p.His105Asn	missense_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3 link	c.313C>A	p.His105Asn	missense_variant	Exon 2 of 2	1		ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1 link	n.208-66666G>T		intron_variant	Intron 2 of 4	1		ENSP00000429902.1	E5RH51
ENSG00000255811	ENST00000542839.1 link	n.110+2913G>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00719

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000562

AC:

141

AN:

250876

AF XY:

0.000413

show subpopulations

Gnomad AFR exome

AF:

0.00739

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000181

AC:

265

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00618

AC:

207

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112012

Other (OTH)

AF:

0.000546

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

100

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

AF:

0.00212

AC:

323

AN:

152286

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00717

AC:

298

AN:

41560

American (AMR)

AF:

0.00144

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00143

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000963

Hom.:

Bravo

AF:

0.00269

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 31, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His105Asn in Exon 02 of GJB3: This variant is not expected to have clinical sign ificance because it has been identified in 0.6% (24/3738) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs150245955). -

Jun 07, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GJB3-related disorder

Benign:1

Jan 02, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.78

D;D

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.75

.;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.0089

T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.2

L;L

PhyloP100

0.88

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.38

Sift

Benign

0.17

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.020

B;B

Vest4

0.10

MVP

0.93

MPC

0.075

ClinPred

0.020

GERP RS

5.8

Varity_R

0.25

gMVP

0.61

Mutation Taster

=98/2

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over