13-20142272-C-T

Variant names:

• chr13-20142272-C-T
• rs11617415
• NM_021954.4:c.1017G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.07
• Publications: 17 publications found

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

ENSG00000299362 (HGNC:):

ACMG classification

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	c.1017G>A	p.Ala339Ala	synonymous_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.1017G>A	p.Ala339Ala	synonymous_variant	Exon 2 of 2		XP_011533350.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30520 AN: 152096 Hom.: 3248 Cov.: 33

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

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.: 41 AF XY: 0.216 AC XY: 150557 AN XY: 697494

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

GnomAD4 genome AF: 0.201 AC: 30535 AN: 152202 Hom.: 3252 Cov.: 33 AF XY: 0.203 AC XY: 15115 AN XY: 74412

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: 97 AN: 290

European-Non Finnish (NFE) AF: 0.209 AC: 14191 AN: 67994

Other (OTH) AF: 0.246 AC: 520 AN: 2110

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

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
DANN	Benign	0.85
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11617415; hg19: chr13-20716411; COSMIC: COSV53834078;