13-20142272-C-T

Variant names:

• chr13-20142272-C-T
• rs11617415
• NM_021954.4:c.1017G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021954.4(GJA3):​c.1017G>A​(p.Ala339Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,561,404 control chromosomes in the GnomAD database, including 36,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3252 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33201 hom.)
• Consequence: GJA3 NM_021954.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.07
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 13-20142272-C-T is Benign according to our data. Variant chr13-20142272-C-T is described in ClinVar as Benign. ClinVar VariationId is 261457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 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.1017G>A	p.Ala339Ala	synonymous	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.1017G>A	p.Ala339Ala	synonymous	Exon 2 of 2	ENSP00000241125.3
	GJA3	ENST00000890229.1		c.1017G>A	p.Ala339Ala	synonymous	Exon 2 of 2	ENSP00000560288.1
	GJA3	ENST00000890230.1		c.1017G>A	p.Ala339Ala	synonymous	Exon 2 of 2	ENSP00000560289.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30520 AN: 152096 Hom.: 3248 Cov.: 33

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.223 AC: 37260 AN: 167114 AF XY: 0.232

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.213 AC: 299747 AN: 1409202 Hom.: 33201 Cov.: 41 AF XY: 0.216 AC XY: 150557 AN XY: 697494

African (AFR) AF: 0.167 AC: 5116 AN: 30696

American (AMR) AF: 0.160 AC: 6093 AN: 38044

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5533 AN: 25136

East Asian (EAS) AF: 0.277 AC: 10017 AN: 36122

South Asian (SAS) AF: 0.300 AC: 24046 AN: 80190

European-Finnish (FIN) AF: 0.183 AC: 8458 AN: 46150

Middle Eastern (MID) AF: 0.300 AC: 1691 AN: 5644

European-Non Finnish (NFE) AF: 0.207 AC: 225428 AN: 1088782

Other (OTH) AF: 0.229 AC: 13365 AN: 58438

GnomAD4 genome AF: 0.201 AC: 30535 AN: 152202 Hom.: 3252 Cov.: 33 AF XY: 0.203 AC XY: 15115 AN XY: 74412

African (AFR) AF: 0.162 AC: 6710 AN: 41530

American (AMR) AF: 0.196 AC: 3004 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 730 AN: 3470

East Asian (EAS) AF: 0.308 AC: 1593 AN: 5166

South Asian (SAS) AF: 0.306 AC: 1477 AN: 4822

European-Finnish (FIN) AF: 0.188 AC: 1992 AN: 10610

Middle Eastern (MID) AF: 0.334 AC: 97 AN: 290

European-Non Finnish (NFE) AF: 0.209 AC: 14191 AN: 67994

Other (OTH) AF: 0.246 AC: 520 AN: 2110

Alfa AF: 0.189 Hom.: 1579

Bravo AF: 0.199

Asia WGS AF: 0.286 AC: 991 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.7
DANN	Benign	0.85
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs11617415; hg19: chr13-20716411; COSMIC: COSV53834078;