rs199689484

chr1-34785102-G-A

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.340G>A(p.Ala114Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,046 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A114D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.674

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=0.012672514).
• BP6: Variant 1-34785102-G-A is Benign according to our data. Variant chr1-34785102-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46083.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000151 (23/152278) while in subpopulation SAS AF= 0.00166 (8/4822). AF 95% confidence interval is 0.000825. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 23 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.340G>A	p.Ala114Thr	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.340G>A	p.Ala114Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.340G>A	p.Ala114Thr	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.340G>A	p.Ala114Thr	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66693C>T		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2886C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000263 AC: 66 AN: 250644 Hom.: 0 AF XY: 0.000347 AC XY: 47 AN XY: 135468

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461768 Hom.: 1 Cov.: 33 AF XY: 0.000199 AC XY: 145 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74458

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000813 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB3 protein function. ClinVar contains an entry for this variant (Variation ID: 46083). This variant has not been reported in the literature in individuals affected with GJB3-related conditions. This variant is present in population databases (rs199689484, gnomAD 0.1%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the GJB3 protein (p.Ala114Thr). 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 23, 2013

Ala114thr in exon 2 of GJB3: This variant is not expected to have clinical signi ficance because computational analyses (biochemical amino acid properties, homol ogy, PolyPhen2, SIFT, AlignGVGD) strongly suggest the variant will not impact th e protein. In addition, this amino acid position is not conserved across species and threonine (Thr) is seen in several primates, mammals and distant species. -

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	0.067
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	2.2
Dann	Benign	0.91
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.024	D
MutationAssessor	Benign	0.45	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.070	N;N
REVEL	Benign	0.24
Sift	Benign	0.63	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0020	B;B
Vest4		0.039
MVP		0.70
MPC		0.063
ClinPred		0.013	T
GERP RS		-3.6
Varity_R		0.052
gMVP		0.61

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: rs199689484; hg19: chr1-35250703; COSMIC: COSV64904623;