rs117385606

Positions:

• chr1-34785342-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024009.3(GJB3):​c.580G>A​(p.Ala194Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0004 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A194D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 4.15

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013227105).
• BP6: Variant 1-34785342-G-A is Benign according to our data. Variant chr1-34785342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 6493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-34785342-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000467 (71/152114) while in subpopulation EAS AF= 0.00641 (33/5150). AF 95% confidence interval is 0.00469. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 71 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3	c.580G>A	p.Ala194Thr	missense_variant	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.580G>A	p.Ala194Thr	missense_variant	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.580G>A	p.Ala194Thr	missense_variant	2/2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.580G>A	p.Ala194Thr	missense_variant	2/2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-66933C>T		intron_variant		1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2646C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 151996 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: 0.00639

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000839 AC: 211 AN: 251398 Hom.: 0 AF XY: 0.000795 AC XY: 108 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00696

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000393 AC: 574 AN: 1461698 Hom.: 0 Cov.: 34 AF XY: 0.000391 AC XY: 284 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00753

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000467 AC: 71 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00641

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000306

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 15469079, 27057829, 20627047, 33126609, 22617145, 24612839, 31015822, 25788563, 20593197, 31541171, 25724631, 30733538, 30245029, 19050930, 20981092, 25262649, 23638949, 22652773) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Deafness, digenic, GJB2/GJB3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675236:Autosomal dominant nonsyndromic hearing loss 2B;C4551486:Erythrokeratodermia variabilis et progressiva 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 18, 2022

- -

Erythrokeratodermia variabilis et progressiva 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.6	N;N
REVEL	Uncertain	0.56
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.16	B;B
Vest4		0.19
MVP		0.90
MPC		0.39
ClinPred		0.039	T
GERP RS		4.2
Varity_R		0.18
gMVP		0.76

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: rs117385606; hg19: chr1-35250943; COSMIC: COSV99055548;