Genetic Variant XR_922079.4:n.82-4168C>T (chr1-147773393-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The XR_922079.4(LOC102723321):n.82-4168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,214 control chromosomes in the GnomAD database, including 3,165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3159 hom., cov: 31)

Exomes 𝑓: 0.17 ( 6 hom. )

Consequence

LOC102723321
XR_922079.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.35

Publications

33 publications found

Variant links:

Genes affected

ENSG00000294222 (HGNC:):

ENSG00000294222 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

BP6

Variant 1-147773393-C-T is Benign according to our data. Variant chr1-147773393-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 368829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000721952.1. 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_005266.7		c.-175G>A		upstream_gene	N/A	NP_005257.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENSG00000294222	ENST00000721952.1		n.386+7274G>A	intron	N/A
ENSG00000294222	ENST00000721953.1		n.388+7274G>A	intron	N/A
GJA5	ENST00000621517.1	TSL:2	c.-175G>A	upstream_gene	N/A	ENSP00000484552.1	P36382

Frequencies

GnomAD3 genomes

AF:

0.187

AC:

28344

AN:

151872

Hom.:

3157

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0586

Gnomad AMI

AF:

0.318

Gnomad AMR

AF:

0.229

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.336

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.109

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.204

GnomAD4 exome

AF:

0.174

AC:

AN:

224

Hom.:

Cov.:

AF XY:

0.169

AC XY:

AN XY:

142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.167

AC:

AN:

East Asian (EAS)

AF:

0.250

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.138

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.202

AC:

AN:

Other (OTH)

AF:

0.200

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.187

AC:

28369

AN:

151990

Hom.:

3159

Cov.:

AF XY:

0.186

AC XY:

13805

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0590

AC:

2446

AN:

41488

American (AMR)

AF:

0.230

AC:

3509

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

628

AN:

3470

East Asian (EAS)

AF:

0.334

AC:

1717

AN:

5144

South Asian (SAS)

AF:

0.176

AC:

848

AN:

4818

European-Finnish (FIN)

AF:

0.230

AC:

2435

AN:

10566

Middle Eastern (MID)

AF:

0.117

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.236

AC:

16032

AN:

67934

Other (OTH)

AF:

0.205

AC:

432

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1109

2217

3326

4434

5543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.109

Hom.:

187

Bravo

AF:

0.185

Asia WGS

AF:

0.246

AC:

854

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial atrial fibrillation (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.4

PromoterAI

-0.045

Neutral

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over