Genetic Variant GJA5:c.-33-1361A>G (chr1-147760632-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005266.7(GJA5):c.-33-1361A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 152,068 control chromosomes in the GnomAD database, including 15,930 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 15920 hom., cov: 32)

Exomes 𝑓: 0.56 ( 10 hom. )

Consequence

GJA5
NM_005266.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.363

Publications

24 publications found

Variant links:

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

GJA5 Gene-Disease associations (from GenCC):

atrial fibrillation, familial, 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
heart conduction disease
Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

GJA5 links:

ENSG00000294222 (HGNC:):

ENSG00000294222 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GJA5	NM_005266.7 link	c.-33-1361A>G	intron_variant	Intron 1 of 1		NP_005257.2	P36382X5D2H9
LOC102723321	XR_922079.4 link	n.82-16929T>C	intron_variant	Intron 1 of 2
GJA5	NM_181703.4 link	c.-167A>G	upstream_gene_variant		ENST00000579774.3	NP_859054.1	P36382X5D2H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3 link	c.-167A>G		upstream_gene_variant		1	NM_181703.4	ENSP00000463851.1		P36382

Frequencies

GnomAD3 genomes

AF:

0.457

AC:

69381

AN:

151900

Hom.:

15874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.547

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.433

Gnomad EAS

AF:

0.549

Gnomad SAS

AF:

0.462

Gnomad FIN

AF:

0.434

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.477

Gnomad OTH

AF:

0.485

GnomAD4 exome

AF:

0.560

AC:

AN:

Hom.:

Cov.:

AF XY:

0.563

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.548

AC:

AN:

Other (OTH)

AF:

0.667

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.457

AC:

69477

AN:

152018

Hom.:

15920

Cov.:

AF XY:

0.457

AC XY:

33991

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.387

AC:

16039

AN:

41418

American (AMR)

AF:

0.536

AC:

8194

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.433

AC:

1504

AN:

3470

East Asian (EAS)

AF:

0.550

AC:

2844

AN:

5172

South Asian (SAS)

AF:

0.462

AC:

2226

AN:

4818

European-Finnish (FIN)

AF:

0.434

AC:

4586

AN:

10576

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.477

AC:

32454

AN:

67974

Other (OTH)

AF:

0.487

AC:

1027

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1951

3903

5854

7806

9757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.470

Hom.:

22408

Bravo

AF:

0.464

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.2

(source)

PhyloP100

-0.36

PromoterAI

-0.075

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-147760632-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over