chr13-20142746-G-A

Position:

• chr13-20142746-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021954.4(GJA3):​c.543C>T​(p.Cys181Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 1,613,678 control chromosomes in the GnomAD database, including 1,469 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (153 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1316 hom.)
• Consequence: GJA3 NM_021954.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0710

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=-0.57).
• BP6: Variant 13-20142746-G-A is Benign according to our data. Variant chr13-20142746-G-A is described in ClinVar as [Benign]. Clinvar id is 261458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20142746-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.071 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0324 (4929/152336) while in subpopulation NFE AF= 0.0415 (2821/68020). AF 95% confidence interval is 0.0402. There are 153 homozygotes in gnomad4. There are 2602 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4929 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA3	NM_021954.4	c.543C>T	p.Cys181Cys	synonymous_variant	2/2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.543C>T	p.Cys181Cys	synonymous_variant	2/2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.543C>T	p.Cys181Cys	synonymous_variant	2/2	3	NM_021954.4	ENSP00000241125.3

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4929 AN: 152218 Hom.: 153 Cov.: 33

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0342 AC: 8576 AN: 250712 Hom.: 318 AF XY: 0.0346 AC XY: 4697 AN XY: 135664

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0215

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00954

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0354 AC: 51742 AN: 1461342 Hom.: 1316 Cov.: 35 AF XY: 0.0350 AC XY: 25414 AN XY: 727008

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0287

GnomAD4 genome AF: 0.0324 AC: 4929 AN: 152336 Hom.: 153 Cov.: 33 AF XY: 0.0349 AC XY: 2602 AN XY: 74488

Gnomad4 AFR AF: 0.00618

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.129

Gnomad4 NFE AF: 0.0415

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0367 Hom.: 76

Bravo AF: 0.0220

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0334

EpiControl AF: 0.0320

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	Aug 17, 2018	- -

Cataract 14 multiple types Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.68

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: rs74607195; hg19: chr13-20716885;