NM_021954.4:c.1017G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021954.4(GJA3):c.1017G>A(p.Ala339Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,561,404 control chromosomes in the GnomAD database, including 36,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3252 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33201 hom. )

Consequence

GJA3
NM_021954.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.07

Publications

17 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=-0.65).

BP6

Variant 13-20142272-C-T is Benign according to our data. Variant chr13-20142272-C-T is described in ClinVar as Benign. ClinVar VariationId is 261457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4 link	c.1017G>A	p.Ala339Ala	synonymous_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2	Q9Y6H8
GJA3	XM_011535048.3 link	c.1017G>A	p.Ala339Ala	synonymous_variant	Exon 2 of 2		XP_011533350.1	Q9Y6H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4 link	c.1017G>A	p.Ala339Ala	synonymous_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3		Q9Y6H8
ENSG00000299362	ENST00000762843.1 link	n.133+4270C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30520

AN:

152096

Hom.:

3248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.243

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.210

Gnomad EAS

AF:

0.308

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.331

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.243

GnomAD2 exomes

AF:

0.223

AC:

37260

AN:

167114

AF XY:

0.232

show subpopulations

Gnomad AFR exome

AF:

0.179

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.313

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.213

AC:

299747

AN:

1409202

Hom.:

33201

Cov.:

AF XY:

0.216

AC XY:

150557

AN XY:

697494

show subpopulations

African (AFR)

AF:

0.167

AC:

5116

AN:

30696

American (AMR)

AF:

0.160

AC:

6093

AN:

38044

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

5533

AN:

25136

East Asian (EAS)

AF:

0.277

AC:

10017

AN:

36122

South Asian (SAS)

AF:

0.300

AC:

24046

AN:

80190

European-Finnish (FIN)

AF:

0.183

AC:

8458

AN:

46150

Middle Eastern (MID)

AF:

0.300

AC:

1691

AN:

5644

European-Non Finnish (NFE)

AF:

0.207

AC:

225428

AN:

1088782

Other (OTH)

AF:

0.229

AC:

13365

AN:

58438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

14194

28388

42581

56775

70969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8004

16008

24012

32016

40020

<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:

0.201

AC:

30535

AN:

152202

Hom.:

3252

Cov.:

AF XY:

0.203

AC XY:

15115

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.162

AC:

6710

AN:

41530

American (AMR)

AF:

0.196

AC:

3004

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.210

AC:

730

AN:

3470

East Asian (EAS)

AF:

0.308

AC:

1593

AN:

5166

South Asian (SAS)

AF:

0.306

AC:

1477

AN:

4822

European-Finnish (FIN)

AF:

0.188

AC:

1992

AN:

10610

Middle Eastern (MID)

AF:

0.334

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.209

AC:

14191

AN:

67994

Other (OTH)

AF:

0.246

AC:

520

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1269

2538

3806

5075

6344

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<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:

0.189

Hom.:

1579

Bravo

AF:

0.199

Asia WGS

AF:

0.286

AC:

991

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cataract 14 multiple types

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.7

(source)

DANN

Benign

0.85

PhyloP100

-1.1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over