rs1114167307

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_021954.4(GJA3):c.56C>T(p.Thr19Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. T19P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GJA3
NM_021954.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.87

Publications

15 publications found

Variant links:

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

GJA3 links:

ENSG00000299362 (HGNC:):

ENSG00000299362 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 2 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;

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, 0.979

PP5

Variant 13-20143233-G-A is Pathogenic according to our data. Variant chr13-20143233-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252944.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 link	c.56C>T	p.Thr19Met	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2	Q9Y6H8
GJA3	XM_011535048.3 link	c.56C>T	p.Thr19Met	missense_variant	Exon 2 of 2		XP_011533350.1	Q9Y6H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4 link	c.56C>T	p.Thr19Met	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3		Q9Y6H8
ENSG00000299362	ENST00000762843.1 link	n.133+5231G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1407970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693420

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32402

American (AMR)

AF:

0.00

AC:

AN:

40316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22266

East Asian (EAS)

AF:

0.00

AC:

AN:

39236

South Asian (SAS)

AF:

0.00

AC:

AN:

76746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083500

Other (OTH)

AF:

0.00

AC:

AN:

58040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental cataract

Pathogenic:2

Jul 29, 2016

Department of Ophthalmology, Flinders University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2021

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Congenital cataracts-facial dysmorphism-neuropathy syndrome

Pathogenic:1

Jun 17, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GJA3 c.56C>T variant is classified as Pathogenic (PS3, PM2, PP3, PP4, PP1_Strong) -

Cataract 14 multiple types

Pathogenic:1

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: PM1, PP1(Moderate), PS4(supporting), PM2(supporting), PP3. Original variant report: PMID:21031021;28839118;36161833;29461512. The cataract phenotype/s reported for this variant are: Posterior polar, nuclear, and dense nuclear. 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

0.93

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.6

PhyloP100

9.9

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.80

Gain of catalytic residue at T19 (P = 0.0037);

MVP

0.98

MPC

2.1

ClinPred

1.0

GERP RS

5.6

Varity_R

0.91

gMVP

0.98

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over