13-20143282-C-T

Variant names:

• chr13-20143282-C-T
• NM_021954.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_021954.4(GJA3):​c.7G>A​(p.Asp3Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000733 in 1,365,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D3Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA3	NM_021954.4	c.7G>A	p.Asp3Asn	missense_variant	Exon 2 of 2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.7G>A	p.Asp3Asn	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.7G>A	p.Asp3Asn	missense_variant	Exon 2 of 2	3	NM_021954.4	ENSP00000241125.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1365148 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 669194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000178

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.5	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.68		Gain of catalytic residue at D3 (P = 0.0334);
MVP		0.92
MPC		2.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.51
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-20717421;