rs864309691

Positions:

• chr13-20143113-G-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.176C>T​(p.Pro59Leu) 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. 12/21 in silico tools predict a damaging 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. P59A) has been classified as 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:6
• Conservation: PhyloP100: 9.87

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr13-20143114-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3064923.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 13-20143113-G-A is Pathogenic according to our data. Variant chr13-20143113-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20143113-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA3	NM_021954.4	c.176C>T	p.Pro59Leu	missense_variant	2/2	ENST00000241125.4
GJA3	XM_011535048.3	c.176C>T	p.Pro59Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA3	ENST00000241125.4	c.176C>T	p.Pro59Leu	missense_variant	2/2	3	NM_021954.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 14 multiple types Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 09, 2019	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in individuals and families with congenital cataracts segregating with disease (PMID: 15208569, 26694549, 19182255, 27609163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 59 of the GJA3 protein (p.Pro59Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -
Pathogenic, 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: PP1(Strong), PS4(Moderate), PM1, PM2(Supporting) PP3. The cataract phenotype/s reported for this variant are: Punctate nuclear, Pulverulent, Lamellar, and Central (Nuclear). Original variant report: PMID:15208569;19182255;21866213;25148791;27609163;26694549;34169787;36161833. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	research	Miami Human Genetics, University Of Miami Miller School Of Medicine	May 09, 2024	- -

Developmental cataract Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	May 01, 2021	- -
Pathogenic, no assertion criteria provided	research	Eye Genetics Research Group, Children's Medical Research Institute	Jan 09, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Gain of catalytic residue at E62 (P = 0.0062);
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
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: rs864309691; hg19: chr13-20717252;