rs74315315

chr1-34784796-G-Achr1-34784796-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PM1 PM5 PP3_Moderate PP5_Moderate BS2

The NM_024009.3(GJB3):c.34G>A(p.Gly12Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 19) in uniprot entity CXB3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_024009.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-34784797-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6483.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 1-34784796-G-A is Pathogenic according to our data. Variant chr1-34784796-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2733870.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-34784796-G-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 13 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.34G>A	p.Gly12Ser	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.34G>A	p.Gly12Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.34G>A	p.Gly12Ser	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.34G>A	p.Gly12Ser	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66387C>T		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+3192C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251314 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135820

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727240

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000543 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2023

This variant is present in population databases (rs74315315, gnomAD 0.03%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt GJB3 protein function. This missense change has been observed in individual(s) with autosomal recessive erythrokeratodermia variabilis (PMID: 29992552). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the GJB3 protein (p.Gly12Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	D;D
Vest4		0.93
MVP		0.99
MPC		0.40
ClinPred		0.43	T
GERP RS		5.8
Varity_R		0.86
gMVP		0.77

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: rs74315315; hg19: chr1-35250397;