rs61734064

chr1-34785360-G-Achr1-34785360-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024009.3(GJB3):c.598G>A(p.Val200Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,613,676 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (163 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (186 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.05

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]

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003349632).
• BP6: Variant 1-34785360-G-A is Benign according to our data. Variant chr1-34785360-G-A is described in ClinVar as [Benign]. Clinvar id is 163535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785360-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.598G>A	p.Val200Ile	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.598G>A	p.Val200Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.598G>A	p.Val200Ile	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.598G>A	p.Val200Ile	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66951C>T		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2628C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3937 AN: 151736 Hom.: 162 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00973

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.00785 AC: 1973 AN: 251422 Hom.: 69 AF XY: 0.00587 AC XY: 797 AN XY: 135880

Gnomad AFR exome AF: 0.0944

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00322 AC: 4700 AN: 1461820 Hom.: 186 Cov.: 33 AF XY: 0.00283 AC XY: 2058 AN XY: 727206

Gnomad4 AFR exome AF: 0.0936

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.0260 AC: 3943 AN: 151856 Hom.: 163 Cov.: 32 AF XY: 0.0254 AC XY: 1884 AN XY: 74182

Gnomad4 AFR AF: 0.0881

Gnomad4 AMR AF: 0.00971

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00556 Hom.: 48

Bravo AF: 0.0296

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0862 AC: 380

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00965 AC: 1172

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Val200Ile in Exon 02 of GJB3: This variant is not expected to have clinical sign ificance because it has been identified in 8.7% (327/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs61734064). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Erythrokeratodermia variabilis et progressiva 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.51	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.17
Sift	Benign	0.19	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.025	B;B
Vest4		0.11
MVP		0.68
MPC		0.074
ClinPred		0.0044	T
GERP RS		2.1
Varity_R		0.065
gMVP		0.51

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

Other links and lift over

dbSNP: rs61734064; hg19: chr1-35250961; COSMIC: COSV64904509;