Genetic Variant GJA5:c.*996T>C (chr1-147757166-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_181703.4(GJA5):c.*996T>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 0.191 in 152,126 control chromosomes in the GnomAD database, including 2,911 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 0.19 ( 2911 hom., cov: 32)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

GJA5
NM_181703.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.58

Publications

8 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
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181703.4. 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
	GJA5	NM_181703.4	MANE Select	c.*996T>C		3_prime_UTR	Exon 2 of 2	NP_859054.1	P36382
	GJA5	NM_005266.7		c.*996T>C		3_prime_UTR	Exon 2 of 2	NP_005257.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GJA5	ENST00000579774.3	TSL:1 MANE Select	c.*996T>C	3_prime_UTR	Exon 2 of 2	ENSP00000463851.1	P36382
GJA5	ENST00000621517.1	TSL:2	c.*996T>C	3_prime_UTR	Exon 2 of 2	ENSP00000484552.1	P36382
GJA5	ENST00000863529.1		c.*996T>C	3_prime_UTR	Exon 2 of 2	ENSP00000533588.1

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

29087

AN:

152004

Hom.:

2906

Cov.:

show subpopulations

Gnomad AFR

AF:

0.171

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.0899

Gnomad SAS

AF:

0.0680

Gnomad FIN

AF:

0.212

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.226

Gnomad OTH

AF:

0.187

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

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)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.191

AC:

29109

AN:

152122

Hom.:

2911

Cov.:

AF XY:

0.185

AC XY:

13757

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.171

AC:

7095

AN:

41494

American (AMR)

AF:

0.157

AC:

2404

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

469

AN:

3472

East Asian (EAS)

AF:

0.0895

AC:

463

AN:

5172

South Asian (SAS)

AF:

0.0686

AC:

331

AN:

4822

European-Finnish (FIN)

AF:

0.212

AC:

2248

AN:

10588

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.226

AC:

15365

AN:

67970

Other (OTH)

AF:

0.185

AC:

392

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1209

2418

3626

4835

6044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.211

Hom.:

12702

Bravo

AF:

0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

PhyloP100

1.6

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over