13-20142272-C-T

Position:

• chr13-20142272-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
GJA3	NM_021954.4	c.1017G>A	p.Ala339Ala	synonymous_variant	2/2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.1017G>A	p.Ala339Ala	synonymous_variant	2/2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.1017G>A	p.Ala339Ala	synonymous_variant	2/2	3	NM_021954.4	ENSP00000241125.3

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

GnomAD3 exomes AF: 0.223 AC: 37260 AN: 167114 Hom.: 4595 AF XY: 0.232 AC XY: 21205 AN XY: 91498

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 SAS exome AF: 0.314

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

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.183

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.229

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

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.308

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.246

Alfa AF: 0.173 Hom.: 944

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2018	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. -

Cataract 14 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Benign	0.85

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

LitVar

Other links and lift over

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