rs74315317

Positions:

• chr1-34785018-T-A
• chr1-34785018-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_024009.3(GJB3):​c.256T>A​(p.Cys86Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.31

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]

ENSG00000255811 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 1-34785018-T-A is Pathogenic according to our data. Variant chr1-34785018-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 6484.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-34785018-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3	c.256T>A	p.Cys86Ser	missense_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.256T>A	p.Cys86Ser	missense_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.256T>A	p.Cys86Ser	missense_variant	2/2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.256T>A	p.Cys86Ser	missense_variant	2/2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-66609A>T		intron_variant		1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2970A>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Erythrokeratodermia variabilis et progressiva 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.54	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.18	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.97	D;D
Vest4		0.82
MutPred		0.88		Gain of glycosylation at P87 (P = 0.0862);Gain of glycosylation at P87 (P = 0.0862);
MVP		0.98
MPC		0.44
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.79

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: rs74315317; hg19: chr1-35250619;