13-20143207-C-T

Variant names:

• chr13-20143207-C-T
• rs1555339539
• NM_021954.4:c.82G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_021954.4(GJA3):​c.82G>A​(p.Val28Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V28L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.80
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_021954.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.7112 (below the threshold of 3.09). Trascript score misZ: -0.026578 (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset nuclear cataract, pulverulent cataract, early-onset posterior polar cataract, cataract 14 multiple types.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 13-20143207-C-T is Pathogenic according to our data. Variant chr13-20143207-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468544.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.82G>A	p.Val28Met	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.82G>A	p.Val28Met	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.82G>A	p.Val28Met	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3
ENSG00000299362	ENST00000762843.1	n.133+5205C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429568 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 706420

African (AFR) AF: 0.00 AC: 0 AN: 33078

American (AMR) AF: 0.00 AC: 0 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.00 AC: 0 AN: 79998

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093992

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cataract 14 multiple types Pathogenic:1 Uncertain:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 28 of the GJA3 protein (p.Val28Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant congenital cataract (PMID: 16254549; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 468544). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GJA3 protein function with a positive predictive value of 95%. This variant disrupts the p.Val28 amino acid residue in GJA3. Other variant(s) that disrupt this residue have been observed in individuals with GJA3-related conditions (PMID: 32384692), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2023

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

Significance: Uncertain significance

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: PM1, PM2(Supporting), PP1, PP3. Original variant report: PMID:16254549. The cataract phenotype/s reported for this variant are: Varied: total, or posterior cortical and anterior capsule, or peripheral cortical. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.76		Gain of catalytic residue at V24 (P = 2e-04);
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.92
Mutation Taster		=12/88	disease causing

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: rs1555339539; hg19: chr13-20717346;