rs786200895

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_024009.3(GJB3):c.196_198delGAC(p.Asp66del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

GJB3
NM_024009.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 9.94

Publications

9 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 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_024009.3. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3 link	c.196_198delGAC	p.Asp66del	conservative_inframe_deletion	Exon 2 of 2	ENST00000373366.3	NP_076872.1	O75712A0A654ICK0
GJB3	NM_001005752.2 link	c.196_198delGAC	p.Asp66del	conservative_inframe_deletion	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.196_198delGAC	p.Asp66del	conservative_inframe_deletion	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2	O75712
GJB3	ENST00000373362.3 link	c.196_198delGAC	p.Asp66del	conservative_inframe_deletion	Exon 2 of 2	1		ENSP00000362460.3	O75712
SMIM12	ENST00000426886.1 link	n.208-66549_208-66547delCGT		intron_variant	Intron 2 of 4	1		ENSP00000429902.1	E5RH51
ENSG00000255811	ENST00000542839.1 link	n.110+3030_110+3032delCGT		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251390

AF XY:

0.0000809

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000814

AC:

119

AN:

1461890

Hom.:

AF XY:

0.0000633

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000358

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:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000773

AC:

AN:

1112012

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

AF:

0.000171

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000217

Hom.:

Bravo

AF:

0.000193

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4

Jun 10, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published in vitro expression studies suggest a damaging effect; a portion of the mutant protein does not reach the cell membrane suggestive of an intracellular trafficking defect and cells shows altered gap junction function, while there was no evidence for an increased rate of cell death in contrast to GJB3 variants associated with skin disorders (PMID: 12165562, 19755382); This variant is associated with the following publications: (PMID: 19755382, 11179004, 12165562, 11758118, 12823303, 29044474, 19197336, 35580552, 36515421, 36147510, 11309368) -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777106179, gnomAD 0.04%). This variant has been observed in individual(s) with hearing impairment and/or neuropathy (PMID: 11309368, 35580552, 36515421). ClinVar contains an entry for this variant (Variation ID: 6490). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB3 function (PMID: 12165562). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 14, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 22, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deafness, autosomal dominant, with peripheral neuropathy

Pathogenic:1

Apr 15, 2001

OMIM

Significance:Pathogenic

Review Status:flagged submission

Collection Method:literature only

- -

not specified

Uncertain:1

Nov 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00014 in 251390 control chromosomes. This frequency does not allow conclusions about variant significance. c.196_198delGAC has been reported in the literature as a dominant mutation in at-least one family with sensorineural hearing loss and peripheral neuropathy (5 genotyped affected transmissions) where it showed both non-segregation (one reference allele transmission to a genotyped affected) and variable penetrance (an unaffected individual with the variant) (example, Lopez-Bigas_2001).These data indicate that the variant may be associated with disease although the authors suggest that other genetic modifiers or environmental factors could contribute to the overall phenotypic spectrum of manifesations. At least two publications report experimental evidence evaluating an impact on protein function evaluating defective channel formation by localization studies and dye transfer experiments, however, do not allow convincing conclusions about the variant effect (example, Di_2002, Tattersall_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Hearing impairment

Uncertain:1

Jun 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PM4 moderate, BS1 strong -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.9

Mutation Taster

=37/63

disease causing (ClinVar)

(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