rs117385606

Variant names:

• chr1-34785342-G-A
• rs117385606
• NM_024009.3:c.580G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 4.15
• Publications: 26 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 -9 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6493.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.580G>A	p.Ala194Thr	missense	Exon 2 of 2	NP_076872.1
	GJB3	NM_001005752.2		c.580G>A	p.Ala194Thr	missense	Exon 2 of 2	NP_001005752.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB3	ENST00000373366.3	TSL:1 MANE Select	c.580G>A	p.Ala194Thr	missense	Exon 2 of 2	ENSP00000362464.2
	GJB3	ENST00000373362.3	TSL:1	c.580G>A	p.Ala194Thr	missense	Exon 2 of 2	ENSP00000362460.3
	SMIM12	ENST00000426886.1	TSL:1	n.208-66933C>T		intron	N/A	ENSP00000429902.1

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

GnomAD2 exomes AF: 0.000839 AC: 211 AN: 251398 AF XY: 0.000795

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.00753 AC: 299 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86256

European-Finnish (FIN) AF: 0.00178 AC: 95 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1111930

Other (OTH) AF: 0.000364 AC: 22 AN: 60390

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

African (AFR) AF: 0.00 AC: 0 AN: 41488

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00641 AC: 33 AN: 5150

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4804

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000354 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Autosomal recessive nonsyndromic hearing loss 1A;C2675236:Autosomal dominant nonsyndromic hearing loss 2B;C4551486:Erythrokeratodermia variabilis et progressiva 1 (2)
1	-	-	Deafness, digenic, GJB2/GJB3 (1)
-	-	1	Erythrokeratodermia variabilis et progressiva 1 (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.6	N
REVEL	Uncertain	0.56
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.16	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
Mutation Taster		=65/35	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: rs117385606; hg19: chr1-35250943; COSMIC: COSV99055548;