NM_021954.4:c.188A>G

Variant names:

• chr13-20143101-T-C
• rs121917823
• NM_021954.4:c.188A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_021954.4(GJA3):​c.188A>G​(p.Asn63Ser) 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. N63K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.15
• Publications: 28 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 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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, 0.969
• PP5: Variant 13-20143101-T-C is Pathogenic according to our data. Variant chr13-20143101-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16978.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021954.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	NM_021954.4	MANE Select	c.188A>G	p.Asn63Ser	missense	Exon 2 of 2	NP_068773.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	ENST00000241125.4	TSL:3 MANE Select	c.188A>G	p.Asn63Ser	missense	Exon 2 of 2	ENSP00000241125.3	Q9Y6H8
	GJA3	ENST00000890229.1		c.188A>G	p.Asn63Ser	missense	Exon 2 of 2	ENSP00000560288.1
	GJA3	ENST00000890230.1		c.188A>G	p.Asn63Ser	missense	Exon 2 of 2	ENSP00000560289.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.000548 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Cataract 14 multiple types (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.80		Gain of catalytic residue at D67 (P = 2e-04)
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.84
gMVP		0.97
Mutation Taster		=8/92	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: rs121917823; hg19: chr13-20717240;