rs121917825

Variant names:

• chr13-20142729-G-A
• rs121917825
• NM_021954.4:c.560C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_021954.4(GJA3):​c.560C>T​(p.Pro187Leu) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P187S) has been classified as Likely 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: 9.85
• Publications: 17 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 13 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, 8 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 chr13-20142730-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1679560.
• 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, 0.964
• PP5: Variant 13-20142729-G-A is Pathogenic according to our data. Variant chr13-20142729-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16980.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.560C>T	p.Pro187Leu	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.560C>T	p.Pro187Leu	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.560C>T	p.Pro187Leu	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3
ENSG00000299362	ENST00000762843.1	n.133+4727G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 14 multiple types Pathogenic:2

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: PP1(Strong), PM2(Supporting), PP3. Original variant report: PMID:10746562. The cataract phenotype reported for this variant is: Pulverulent nuclear with snowflake-like cortical opacity and a posterior subcapsular element. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.69		Gain of catalytic residue at P185 (P = 0.0017);
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.81
gMVP		0.95
Mutation Taster		=10/90	disease causing (ClinVar)

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: rs121917825; hg19: chr13-20716868;