13-20139512-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021954.4(GJA3):c.*2469T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,184 control chromosomes in the GnomAD database, including 3,339 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (3339 hom., cov: 31)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: GJA3 NM_021954.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.219

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-20139512-A-G is Benign according to our data. Variant chr13-20139512-A-G is described in ClinVar as [Benign]. Clinvar id is 311297.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA3	NM_021954.4	c.*2469T>C		3_prime_UTR_variant	2/2	ENST00000241125.4
GJA3	XM_011535048.3	c.*2469T>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA3	ENST00000241125.4	c.*2469T>C		3_prime_UTR_variant	2/2	3	NM_021954.4	P1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27242 AN: 152060 Hom.: 3331 Cov.: 31

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0974

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.500 AC: 3 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.179 AC: 27277 AN: 152178 Hom.: 3339 Cov.: 31 AF XY: 0.179 AC XY: 13302 AN XY: 74384

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.0985

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0975

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.138

Alfa AF: 0.160 Hom.: 612

Bravo AF: 0.176

Asia WGS AF: 0.0620 AC: 217 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 14 multiple types Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.28
Dann	Benign	0.53

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: rs60759737; hg19: chr13-20713651;