13-20141738-C-T

Variant names:

• chr13-20141738-C-T
• rs4769953
• NM_021954.4:c.*243G>A

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.*243G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 576,040 control chromosomes in the GnomAD database, including 18,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3724 hom., cov: 31)
  • Exomes 𝑓: 0.24 (14598 hom.)
• Consequence: GJA3 NM_021954.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.523
• Publications: 9 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=-0.77).
• BP6: Variant 13-20141738-C-T is Benign according to our data. Variant chr13-20141738-C-T is described in ClinVar as Benign. ClinVar VariationId is 311327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021954.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	NM_021954.4	MANE Select	c.*243G>A		3_prime_UTR	Exon 2 of 2	NP_068773.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	ENST00000241125.4	TSL:3 MANE Select	c.*243G>A		3_prime_UTR	Exon 2 of 2	ENSP00000241125.3
	ENSG00000299362	ENST00000762843.1		n.133+3736C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29718 AN: 151828 Hom.: 3728 Cov.: 31

Gnomad AFR AF: 0.0695

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.239

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.243 AC: 103252 AN: 424094 Hom.: 14598 Cov.: 5 AF XY: 0.246 AC XY: 53999 AN XY: 219788

African (AFR) AF: 0.0678 AC: 699 AN: 10304

American (AMR) AF: 0.393 AC: 5915 AN: 15064

Ashkenazi Jewish (ASJ) AF: 0.238 AC: 2977 AN: 12534

East Asian (EAS) AF: 0.501 AC: 13493 AN: 26958

South Asian (SAS) AF: 0.315 AC: 10754 AN: 34130

European-Finnish (FIN) AF: 0.229 AC: 6161 AN: 26862

Middle Eastern (MID) AF: 0.190 AC: 356 AN: 1878

European-Non Finnish (NFE) AF: 0.212 AC: 57502 AN: 271632

Other (OTH) AF: 0.218 AC: 5395 AN: 24732

GnomAD4 genome AF: 0.196 AC: 29708 AN: 151946 Hom.: 3724 Cov.: 31 AF XY: 0.202 AC XY: 15036 AN XY: 74270

African (AFR) AF: 0.0695 AC: 2883 AN: 41504

American (AMR) AF: 0.322 AC: 4922 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 829 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2184 AN: 5112

South Asian (SAS) AF: 0.327 AC: 1570 AN: 4798

European-Finnish (FIN) AF: 0.224 AC: 2367 AN: 10566

Middle Eastern (MID) AF: 0.154 AC: 45 AN: 292

European-Non Finnish (NFE) AF: 0.211 AC: 14353 AN: 67918

Other (OTH) AF: 0.177 AC: 374 AN: 2108

Alfa AF: 0.221 Hom.: 2781

Bravo AF: 0.199

Asia WGS AF: 0.352 AC: 1224 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.8
DANN	Benign	0.82
PhyloP100		0.52
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: rs4769953; hg19: chr13-20715877; COSMIC: COSV53835058;