dbSNP rs74607195: GJA3:p.Cys181Cys (chr13-20142746-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021954.4(GJA3):c.543C>T(p.Cys181Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,613,678 control chromosomes in the GnomAD database, including 1,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 153 hom., cov: 33)

Exomes 𝑓: 0.035 ( 1316 hom. )

Consequence

GJA3
NM_021954.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0710

Publications

7 publications found

Variant links:

Genes affected

GJA3 (HGNC:4277): (gap junction protein alpha 3) The protein encoded by this gene is a connexin and is a component of lens fiber gap junctions. Defects in this gene are a cause of zonular pulverulent cataract type 3 (CZP3). [provided by RefSeq, Jan 2010]

GJA3 Gene-Disease associations (from GenCC):

cataract 14 multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJA3 links:

ENSG00000299362 (HGNC:):

ENSG00000299362 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 13-20142746-G-A is Benign according to our data. Variant chr13-20142746-G-A is described in ClinVar as Benign. ClinVar VariationId is 261458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.071 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0324 (4929/152336) while in subpopulation NFE AF = 0.0415 (2821/68020). AF 95% confidence interval is 0.0402. There are 153 homozygotes in GnomAd4. There are 2602 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 4929 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021954.4. 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
	GJA3	NM_021954.4	MANE Select	c.543C>T	p.Cys181Cys	synonymous	Exon 2 of 2	NP_068773.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJA3	ENST00000241125.4	TSL:3 MANE Select	c.543C>T	p.Cys181Cys	synonymous	Exon 2 of 2	ENSP00000241125.3	Q9Y6H8
GJA3	ENST00000890229.1		c.543C>T	p.Cys181Cys	synonymous	Exon 2 of 2	ENSP00000560288.1
GJA3	ENST00000890230.1		c.543C>T	p.Cys181Cys	synonymous	Exon 2 of 2	ENSP00000560289.1

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4929

AN:

152218

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00620

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00889

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0415

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0342

AC:

8576

AN:

250712

AF XY:

0.0346

show subpopulations

Gnomad AFR exome

AF:

0.00457

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.126

Gnomad NFE exome

AF:

0.0413

Gnomad OTH exome

AF:

0.0391

GnomAD4 exome

AF:

0.0354

AC:

51742

AN:

1461342

Hom.:

1316

Cov.:

AF XY:

0.0350

AC XY:

25414

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.00469

AC:

157

AN:

33478

American (AMR)

AF:

0.0110

AC:

490

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0230

AC:

601

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0104

AC:

893

AN:

86258

European-Finnish (FIN)

AF:

0.128

AC:

6788

AN:

53042

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0369

AC:

41036

AN:

1111864

Other (OTH)

AF:

0.0287

AC:

1734

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

3218

6435

9653

12870

16088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1402

2804

4206

5608

7010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0324

AC:

4929

AN:

152336

Hom.:

153

Cov.:

AF XY:

0.0349

AC XY:

2602

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00618

AC:

257

AN:

41596

American (AMR)

AF:

0.0200

AC:

306

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0239

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00890

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.129

AC:

1363

AN:

10600

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0415

AC:

2821

AN:

68020

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

248

496

743

991

1239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0380

Hom.:

204

Bravo

AF:

0.0220

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0334

EpiControl

AF:

0.0320

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cataract 14 multiple types (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.7

(source)

DANN

Benign

0.68

PhyloP100

0.071

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over