rs149933083

Variant names:

• chr13-20142891-C-T
• rs149933083
• NM_021954.4:c.398G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-20142891-C-T
• chr13-20142891-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021954.4(GJA3):​c.398G>A​(p.Arg133Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00307 in 1,596,504 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.82
• Publications: 5 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=0.0066975057).
• BP6: Variant 13-20142891-C-T is Benign according to our data. Variant chr13-20142891-C-T is described in ClinVar as Benign. ClinVar VariationId is 311346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00291 (444/152336) while in subpopulation AMR AF = 0.00431 (66/15310). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 444 AD gene.

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.398G>A	p.Arg133Gln	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.398G>A	p.Arg133Gln	missense	Exon 2 of 2	ENSP00000241125.3	Q9Y6H8
	GJA3	ENST00000890229.1		c.398G>A	p.Arg133Gln	missense	Exon 2 of 2	ENSP00000560288.1
	GJA3	ENST00000890230.1		c.398G>A	p.Arg133Gln	missense	Exon 2 of 2	ENSP00000560289.1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00319 AC: 687 AN: 215698 AF XY: 0.00328

Gnomad AFR exome AF: 0.000610

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00888

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00308 AC: 4455 AN: 1444168 Hom.: 12 Cov.: 35 AF XY: 0.00304 AC XY: 2181 AN XY: 717080

African (AFR) AF: 0.000635 AC: 21 AN: 33060

American (AMR) AF: 0.00282 AC: 116 AN: 41142

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 344 AN: 25822

East Asian (EAS) AF: 0.00 AC: 0 AN: 38716

South Asian (SAS) AF: 0.000485 AC: 41 AN: 84506

European-Finnish (FIN) AF: 0.00930 AC: 484 AN: 52038

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5752

European-Non Finnish (NFE) AF: 0.00293 AC: 3232 AN: 1103386

Other (OTH) AF: 0.00350 AC: 209 AN: 59746

GnomAD4 genome AF: 0.00291 AC: 444 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.00314 AC XY: 234 AN XY: 74484

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.00431 AC: 66 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00913 AC: 97 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00334 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00246 AC: 296

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0067	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.33
Sift	Benign	0.056	T
Sift4G	Uncertain	0.060	T
Polyphen		0.36	B
Vest4		0.28
MVP		0.84
MPC		1.2
ClinPred		0.018	T
GERP RS		3.7
Varity_R		0.15
gMVP		0.76
Mutation Taster		=85/15	polymorphism

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: rs149933083; hg19: chr13-20717030;