rs1886176

Positions:

• chr13-20141662-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021954.4(GJA3):​c.*319G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 380,100 control chromosomes in the GnomAD database, including 12,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4789 hom., cov: 30)
  • Exomes 𝑓: 0.24 (7378 hom.)
• Consequence: GJA3 NM_021954.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.628

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-20141662-C-A is Benign according to our data. Variant chr13-20141662-C-A is described in ClinVar as [Benign]. Clinvar id is 311326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA3	NM_021954.4	c.*319G>T		3_prime_UTR_variant	2/2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.*319G>T		3_prime_UTR_variant	2/2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.*319G>T		3_prime_UTR_variant	2/2	3	NM_021954.4	ENSP00000241125	P1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37608 AN: 151704 Hom.: 4783 Cov.: 30

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.243 AC: 55563 AN: 228278 Hom.: 7378 Cov.: 2 AF XY: 0.244 AC XY: 28462 AN XY: 116710

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.185

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.280

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.255

GnomAD4 genome AF: 0.248 AC: 37631 AN: 151822 Hom.: 4789 Cov.: 30 AF XY: 0.248 AC XY: 18366 AN XY: 74158

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.229

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.282

Alfa AF: 0.266 Hom.: 8863

Bravo AF: 0.245

Asia WGS AF: 0.291 AC: 1012 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 03, 2018	- -

Cataract 14 multiple types Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.78

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: rs1886176; hg19: chr13-20715801;