rs140332366

Positions:

• chr13-20142726-T-A
• chr13-20142726-T-C
• chr13-20142726-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_021954.4(GJA3):​c.563A>T​(p.Asn188Ile) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.84

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 27) in uniprot entity CXA3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021954.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA3	NM_021954.4	c.563A>T	p.Asn188Ile	missense_variant	2/2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.563A>T	p.Asn188Ile	missense_variant	2/2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.563A>T	p.Asn188Ile	missense_variant	2/2	3	NM_021954.4	ENSP00000241125	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 14 multiple types Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	Jan 21, 2023	Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PM2(Supporting), PM5(Supporting), PP1, PP3. Original variant report: PMID:22312188. The cataract phenotype reported for this variant is: Nuclear dense coralliform with fine blue dust-like opacities in cortical zone. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.62		Gain of catalytic residue at P185 (P = 0);
MVP		0.95
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.99

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: rs140332366; hg19: chr13-20716865;