rs1886176

Variant names:

• chr13-20141662-C-A
• rs1886176
• NM_021954.4:c.*319G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 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 -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 VariationId 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 rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.*319G>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.*319G>T		3_prime_UTR_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.*319G>T		3_prime_UTR_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3
ENSG00000299362	ENST00000762843.1	n.133+3660C>A		intron_variant	Intron 1 of 1

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

African (AFR) AF: 0.197 AC: 1213 AN: 6146

American (AMR) AF: 0.185 AC: 1625 AN: 8804

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 1690 AN: 7860

East Asian (EAS) AF: 0.280 AC: 4518 AN: 16144

South Asian (SAS) AF: 0.218 AC: 3419 AN: 15712

European-Finnish (FIN) AF: 0.221 AC: 2949 AN: 13318

Middle Eastern (MID) AF: 0.300 AC: 337 AN: 1124

European-Non Finnish (NFE) AF: 0.250 AC: 36069 AN: 144468

Other (OTH) AF: 0.255 AC: 3743 AN: 14702

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

African (AFR) AF: 0.204 AC: 8445 AN: 41392

American (AMR) AF: 0.229 AC: 3490 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3466

East Asian (EAS) AF: 0.350 AC: 1798 AN: 5138

South Asian (SAS) AF: 0.264 AC: 1266 AN: 4800

European-Finnish (FIN) AF: 0.243 AC: 2565 AN: 10540

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18326 AN: 67900

Other (OTH) AF: 0.282 AC: 595 AN: 2108

Alfa AF: 0.260 Hom.: 20517

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cataract 14 multiple types Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.78
PhyloP100		0.63
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: rs1886176; hg19: chr13-20715801;