rs398122937

Variant names:

• chr13-20142862-C-T
• rs398122937
• NM_021954.4:c.427G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_021954.4(GJA3):​c.427G>A​(p.Gly143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G143E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.74

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a disulfide_bond (size 138) in uniprot entity CXA3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_021954.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 13-20142862-C-T is Pathogenic according to our data. Variant chr13-20142862-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.427G>A	p.Gly143Arg	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.427G>A	p.Gly143Arg	missense_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.427G>A	p.Gly143Arg	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 14 multiple types Pathogenic:3

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 21, 2023

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Supporting), PM2(Supporting), PP3. Original variant report: PMID:22876138;34169787. The cataract phenotype reported for this variant is: Pulverulent disk-like (Coppock). Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the GJA3 protein (p.Gly143Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 22876138). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 50945). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJA3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJA3 function (PMID: 24019978). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.65		Gain of MoRF binding (P = 0.0255);
MVP		0.86
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.80
gMVP		0.98

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: rs398122937; hg19: chr13-20717001;