chr13-20142891-C-G

Position:

• chr13-20142891-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_021954.4(GJA3):​c.398G>C​(p.Arg133Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,444,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R133Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.82

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 3 ACMG points.

• PM1: In a disulfide_bond (size 138) in uniprot entity CXA3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_021954.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4146495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA3	NM_021954.4	c.398G>C	p.Arg133Pro	missense_variant	2/2	ENST00000241125.4	NP_068773.2
GJA3	XM_011535048.3	c.398G>C	p.Arg133Pro	missense_variant	2/2		XP_011533350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4	c.398G>C	p.Arg133Pro	missense_variant	2/2	3	NM_021954.4	ENSP00000241125.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444172 Hom.: 0 Cov.: 35 AF XY: 0.00000279 AC XY: 2 AN XY: 717082

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.51	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.0065	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.38
Sift	Benign	0.087	T
Sift4G	Benign	0.083	T
Polyphen		0.32	B
Vest4		0.19
MutPred		0.43		Gain of catalytic residue at G137 (P = 0.0077);
MVP		0.87
MPC		1.4
ClinPred		0.68	D
GERP RS		3.7
Varity_R		0.48
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs149933083; hg19: chr13-20717030;