Genetic Variant GJA3:p.Ala339Ala (chr13-20142272-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BS1BS2

The NM_021954.4(GJA3):c.1017G>C(p.Ala339Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,561,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A339A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GJA3
NM_021954.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP7

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

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000854 (13/152232) while in subpopulation AFR AF = 0.000313 (13/41538). AF 95% confidence interval is 0.000185. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4 link	c.1017G>C	p.Ala339Ala	synonymous_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2	Q9Y6H8
GJA3	XM_011535048.3 link	c.1017G>C	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>C	p.Ala339Ala	synonymous_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3		Q9Y6H8
ENSG00000299362	ENST00000762843.1 link	n.133+4270C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

167114

AF XY:

0.0000437

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000436

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000263

AC:

AN:

1409448

Hom.:

Cov.:

AF XY:

0.0000201

AC XY:

AN XY:

697626

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

30702

American (AMR)

AF:

0.00

AC:

AN:

38064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25140

East Asian (EAS)

AF:

0.00

AC:

AN:

36130

South Asian (SAS)

AF:

0.00

AC:

AN:

80230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.0000220

AC:

AN:

1088902

Other (OTH)

AF:

0.0000342

AC:

AN:

58444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41538

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

1579

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.48

(source)

DANN

Benign

0.48

PhyloP100

-1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over