rs200055020

chr1-34785241-G-Achr1-34785241-G-Cchr1-34785241-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024009.3(GJB3):c.479G>A(p.Arg160His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000781 in 1,613,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 7.95

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019035876).
• BP6: Variant 1-34785241-G-A is Benign according to our data. Variant chr1-34785241-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178351.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=1}. Variant chr1-34785241-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000526 (80/152142) while in subpopulation AMR AF= 0.00144 (22/15288). AF 95% confidence interval is 0.000973. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 80 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.479G>A	p.Arg160His	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.479G>A	p.Arg160His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.479G>A	p.Arg160His	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.479G>A	p.Arg160His	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66832C>T		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2747C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00159 AC: 399 AN: 251364 Hom.: 0 AF XY: 0.00136 AC XY: 185 AN XY: 135890

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000616

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000807 AC: 1180 AN: 1461734 Hom.: 1 Cov.: 34 AF XY: 0.000788 AC XY: 573 AN XY: 727192

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00776

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000719

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74384

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000487 Hom.: 0

Bravo AF: 0.00107

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Has been observed at GeneDx in two unrelated individuals with hearing loss with pathogenic GJB2 variants -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2014

Variant classified as Uncertain Significance - Favor Benign. The p.Arg160His var iant in GJB3 has not been previously reported in individuals with hearing loss, but has been identified in 4/8600 European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/) and in 0.8% (1/128) of Mexican ancestry chromosomes by the 1000 Genomes Project (dbSNP rs200055020). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg160His var iant is uncertain, the frequency data suggest that it is more likely to be benig n. -

GJB3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2020

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). -

Erythrokeratodermia variabilis et progressiva 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Uncertain	0.69	D;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.019	T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.26	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.63	P;P
Vest4		0.69
MVP		0.95
MPC		0.43
ClinPred		0.058	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.76

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: rs200055020; hg19: chr1-35250842; COSMIC: COSV64904443;