1-34785055-G-C

Position:

• chr1-34785055-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024009.3(GJB3):​c.293G>C​(p.Arg98Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3	c.293G>C	p.Arg98Pro	missense_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.293G>C	p.Arg98Pro	missense_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.293G>C	p.Arg98Pro	missense_variant	2/2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.293G>C	p.Arg98Pro	missense_variant	2/2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-66646C>G		intron_variant		1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2933C>G		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251114 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135726

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.70		Gain of glycosylation at R98 (P = 0.0188);Gain of glycosylation at R98 (P = 0.0188);
MVP		1.0
MPC		0.47
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.96

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: rs201314683; hg19: chr1-35250656;