rs864309694

chr13-20143282-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_021954.4(GJA3):c.7G>C(p.Asp3His) variant causes a missense change. 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. D3Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.08

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 12 ACMG points.

• PM1: In a intramembrane_region (size 13) in uniprot entity CXA3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr13-20143282-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2735992.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 13-20143282-C-G is Pathogenic according to our data. Variant chr13-20143282-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217343.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA3	NM_021954.4	c.7G>C	p.Asp3His	missense_variant	2/2	ENST00000241125.4
GJA3	XM_011535048.3	c.7G>C	p.Asp3His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA3	ENST00000241125.4	c.7G>C	p.Asp3His	missense_variant	2/2	3	NM_021954.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 14 multiple types Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 22, 2022

This sequence change is predicted to replace aspartic acid with histidine at codon 3 of the GJA3 protein, p.(Asp3His). The aspartic acid residue is highly conserved (100 vertebrates, UCSC), and is located in the connexin domain at a residue essential for correct voltage sensitivity of the gap junction hemichannels/channels (PMID: 22843197). Furthermore, there is a moderate physicochemical difference between aspartic acid and histidine, including a change in charge from negative to positive which is likely to result in a loss of channel voltage sensitivity. The variant is absent in a large population cohort (gnomAD v2.1), and has been identified in at least two cases with congenital cataracts (Royal Melbourne Hospital; PMID: 26694549). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Additionally, a different missense change (p.Asp3Tyr) determined to be pathogenic has been seen before (PMID: 29934635, 16885921, 22843197). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2, PS4_Supporting, PP3. -

Developmental cataract Pathogenic:1

Likely 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	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.70		Gain of catalytic residue at S5 (P = 0.0646);
MVP		0.94
MPC		2.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.81
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864309694; hg19: chr13-20717421;