13-20142891-C-T

Position:

chr13-20142891-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.82

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

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 id is 311346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20142891-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA3	NM_021954.4 link	c.398G>A	p.Arg133Gln	missense_variant	2/2	ENST00000241125.4	NP_068773.2	Q9Y6H8
GJA3	XM_011535048.3 link	c.398G>A	p.Arg133Gln	missense_variant	2/2		XP_011533350.1	Q9Y6H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA3	ENST00000241125.4 link	c.398G>A	p.Arg133Gln	missense_variant	2/2	3	NM_021954.4	ENSP00000241125.3		Q9Y6H8

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

443

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00319

AC:

687

AN:

215698

Hom.:

AF XY:

0.00328

AC XY:

384

AN XY:

116946

show subpopulations

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 SAS exome

AF:

0.000391

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.:

Cov.:

AF XY:

0.00304

AC XY:

2181

AN XY:

717080

show subpopulations

Gnomad4 AFR exome

AF:

0.000635

Gnomad4 AMR exome

AF:

0.00282

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000485

Gnomad4 FIN exome

AF:

0.00930

Gnomad4 NFE exome

AF:

0.00293

Gnomad4 OTH exome

AF:

0.00350

GnomAD4 genome

AF:

0.00291

AC:

444

AN:

152336

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00431

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00913

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00385

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00246

AC:

296

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cataract 14 multiple types

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0067

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.33

Sift

Benign

0.056

Sift4G

Uncertain

0.060

Polyphen

0.36

Vest4

0.28

MVP

0.84

MPC

1.2

ClinPred

0.018

GERP RS

3.7

Varity_R

0.15

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over