rs35983826

Variant names:

• chr1-34785560-C-T
• rs35983826
• NM_024009.3:c.798C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024009.3(GJB3):​c.798C>T​(p.Asn266Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0897 in 1,613,610 control chromosomes in the GnomAD database, including 7,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (666 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6442 hom.)
• Consequence: GJB3 NM_024009.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.335
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-34785560-C-T is Benign according to our data. Variant chr1-34785560-C-T is described in ClinVar as Benign. ClinVar VariationId is 46087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.335 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024009.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	NM_024009.3	MANE Select	c.798C>T	p.Asn266Asn	synonymous	Exon 2 of 2	NP_076872.1	O75712
	GJB3	NM_001005752.2		c.798C>T	p.Asn266Asn	synonymous	Exon 2 of 2	NP_001005752.1	O75712

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	ENST00000373366.3	TSL:1 MANE Select	c.798C>T	p.Asn266Asn	synonymous	Exon 2 of 2	ENSP00000362464.2	O75712
	GJB3	ENST00000373362.3	TSL:1	c.798C>T	p.Asn266Asn	synonymous	Exon 2 of 2	ENSP00000362460.3	O75712
	SMIM12	ENST00000426886.1	TSL:1	n.208-67151G>A		intron	N/A	ENSP00000429902.1	E5RH51

Frequencies

GnomAD3 genomes AF: 0.0899 AC: 13673 AN: 152072 Hom.: 666 Cov.: 32

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0971

GnomAD2 exomes AF: 0.0878 AC: 22017 AN: 250664 AF XY: 0.0915

Gnomad AFR exome AF: 0.0792

Gnomad AMR exome AF: 0.0515

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.00136

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.0997

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0897 AC: 131121 AN: 1461420 Hom.: 6442 Cov.: 34 AF XY: 0.0916 AC XY: 66605 AN XY: 727030

African (AFR) AF: 0.0772 AC: 2585 AN: 33472

American (AMR) AF: 0.0540 AC: 2415 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2650 AN: 26134

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39700

South Asian (SAS) AF: 0.117 AC: 10074 AN: 86236

European-Finnish (FIN) AF: 0.118 AC: 6317 AN: 53398

Middle Eastern (MID) AF: 0.112 AC: 645 AN: 5750

European-Non Finnish (NFE) AF: 0.0908 AC: 100936 AN: 1111646

Other (OTH) AF: 0.0904 AC: 5456 AN: 60362

GnomAD4 genome AF: 0.0898 AC: 13674 AN: 152190 Hom.: 666 Cov.: 32 AF XY: 0.0902 AC XY: 6712 AN XY: 74402

African (AFR) AF: 0.0782 AC: 3247 AN: 41544

American (AMR) AF: 0.0715 AC: 1094 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 352 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5158

South Asian (SAS) AF: 0.111 AC: 535 AN: 4820

European-Finnish (FIN) AF: 0.122 AC: 1293 AN: 10578

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6840 AN: 68004

Other (OTH) AF: 0.0961 AC: 203 AN: 2112

Alfa AF: 0.0983 Hom.: 450

Bravo AF: 0.0827

Asia WGS AF: 0.0640 AC: 221 AN: 3478

EpiCase AF: 0.101

EpiControl AF: 0.0955

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Erythrokeratodermia variabilis et progressiva 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.63
DANN	Benign	0.77
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs35983826; hg19: chr1-35251161; COSMIC: COSV108219568;