rs968566

Variant names:

• chr13-20142394-G-T
• rs968566
• NM_021954.4:c.895C>A

Your query was ambiguous. Multiple possible variants found:

• chr13-20142394-G-T
• chr13-20142394-G-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_021954.4(GJA3):​c.895C>A​(p.Leu299Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,514,404 control chromosomes in the GnomAD database, including 748,458 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71596 hom., cov: 35)
  • Exomes 𝑓: 1.0 (676862 hom.)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.121
• Publications: 30 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=6.86092E-7).
• BP6: Variant 13-20142394-G-T is Benign according to our data. Variant chr13-20142394-G-T is described in ClinVar as Benign. ClinVar VariationId is 261459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.895C>A	p.Leu299Met	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.895C>A	p.Leu299Met	missense	Exon 2 of 2	ENSP00000241125.3	Q9Y6H8
	GJA3	ENST00000890229.1		c.895C>A	p.Leu299Met	missense	Exon 2 of 2	ENSP00000560288.1
	GJA3	ENST00000890230.1		c.895C>A	p.Leu299Met	missense	Exon 2 of 2	ENSP00000560289.1

Frequencies

GnomAD3 genomes AF: 0.968 AC: 147384 AN: 152182 Hom.: 71549 Cov.: 35

Gnomad AFR AF: 0.893

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.973

GnomAD2 exomes AF: 0.991 AC: 120664 AN: 121768 AF XY: 0.993

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.990

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.997 AC: 1357699 AN: 1362114 Hom.: 676862 Cov.: 60 AF XY: 0.997 AC XY: 667357 AN XY: 669260

African (AFR) AF: 0.890 AC: 26858 AN: 30178

American (AMR) AF: 0.989 AC: 27775 AN: 28070

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 22626 AN: 22626

East Asian (EAS) AF: 1.00 AC: 35456 AN: 35456

South Asian (SAS) AF: 1.00 AC: 72799 AN: 72812

European-Finnish (FIN) AF: 1.00 AC: 46989 AN: 46990

Middle Eastern (MID) AF: 0.993 AC: 5437 AN: 5474

European-Non Finnish (NFE) AF: 1.00 AC: 1064019 AN: 1064284

Other (OTH) AF: 0.991 AC: 55740 AN: 56224

GnomAD4 genome AF: 0.968 AC: 147485 AN: 152290 Hom.: 71596 Cov.: 35 AF XY: 0.969 AC XY: 72124 AN XY: 74458

African (AFR) AF: 0.893 AC: 37097 AN: 41554

American (AMR) AF: 0.984 AC: 15063 AN: 15310

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5164

South Asian (SAS) AF: 1.00 AC: 4829 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.993 AC: 290 AN: 292

European-Non Finnish (NFE) AF: 0.999 AC: 67980 AN: 68022

Other (OTH) AF: 0.974 AC: 2060 AN: 2116

Alfa AF: 0.991 Hom.: 161523

Bravo AF: 0.964

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.907 AC: 3805

ESP6500EA AF: 0.999 AC: 8267

ExAC AF: 0.988 AC: 96948

Asia WGS AF: 0.994 AC: 3448 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cataract 14 multiple types (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0040
DANN	Benign	0.10
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.8
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.096	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-0.12
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.14
Sift	Benign	0.47	T
Sift4G	Benign	0.37	T
Polyphen		0.0080	B
Vest4		0.014
MPC		0.89
ClinPred		0.0057	T
GERP RS		-8.6
Varity_R		0.057
gMVP		0.25
Mutation Taster		=99/1	polymorphism (auto)

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: rs968566; hg19: chr13-20716533; COSMIC: COSV53835652;