rs74315319

Variant names:

• chr1-34785300-C-A
• rs74315319
• NM_024009.3:c.538C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-34785300-C-A
• chr1-34785300-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_024009.3(GJB3):​c.538C>A​(p.Arg180Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GJB3 NM_024009.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 90 publications found

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

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB3	NM_024009.3	c.538C>A	p.Arg180Arg	synonymous_variant	Exon 2 of 2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.538C>A	p.Arg180Arg	synonymous_variant	Exon 2 of 2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.538C>A	p.Arg180Arg	synonymous_variant	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.538C>A	p.Arg180Arg	synonymous_variant	Exon 2 of 2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-66891G>T		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2688G>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151842 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74140

African (AFR) AF: 0.00 AC: 0 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2094

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs74315319; hg19: chr1-35250901;