13-20142891-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_021954.4(GJA3):c.398G>A(p.Arg133Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00307 in 1,596,504 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 12 hom. )

Consequence

GJA3
NM_021954.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.82

Publications

5 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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.7112 (below the threshold of 3.09). Trascript score misZ: -0.026578 (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset nuclear cataract, pulverulent cataract, early-onset posterior polar cataract, cataract 14 multiple types.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066975057).

BP6

Variant 13-20142891-C-T is Benign according to our data. Variant chr13-20142891-C-T is described in ClinVar as Benign. ClinVar VariationId is 311346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00291 (444/152336) while in subpopulation AMR AF = 0.00431 (66/15310). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 444 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	NM_021954.4	MANE Select	c.398G>A	p.Arg133Gln	missense	Exon 2 of 2	NP_068773.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	ENST00000241125.4	TSL:3 MANE Select	c.398G>A	p.Arg133Gln	missense	Exon 2 of 2	ENSP00000241125.3
	ENSG00000299362	ENST00000762843.1		n.133+4889C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

443

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00432

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00913

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00319

AC:

687

AN:

215698

AF XY:

0.00328

show subpopulations

Gnomad AFR exome

AF:

0.000610

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00888

Gnomad NFE exome

AF:

0.00279

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00308

AC:

4455

AN:

1444168

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2181

AN XY:

717080

show subpopulations

African (AFR)

AF:

0.000635

AC:

AN:

33060

American (AMR)

AF:

0.00282

AC:

116

AN:

41142

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

344

AN:

25822

East Asian (EAS)

AF:

0.00

AC:

AN:

38716

South Asian (SAS)

AF:

0.000485

AC:

AN:

84506

European-Finnish (FIN)

AF:

0.00930

AC:

484

AN:

52038

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00293

AC:

3232

AN:

1103386

Other (OTH)

AF:

0.00350

AC:

209

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

282

564

847

1129

1411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00291

AC:

444

AN:

152336

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41574

American (AMR)

AF:

0.00431

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00913

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

68032

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00334

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00246

AC:

296

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cataract 14 multiple types

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0067

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

PhyloP100

3.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.33

Sift

Benign

0.056

Sift4G

Uncertain

0.060

Polyphen

0.36

Vest4

0.28

MVP

0.84

MPC

1.2

ClinPred

0.018

GERP RS

3.7

Varity_R

0.15

gMVP

0.76

Mutation Taster

=85/15

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over