dbSNP rs2288713: APAF1:c.3084+93A>C (chr12-98715645-A-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_181861.2(APAF1):c.3084+93A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,424,444 control chromosomes in the GnomAD database, including 8,218 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 0.084 ( 723 hom., cov: 31)

Exomes 𝑓: 0.10 ( 7495 hom. )

Consequence

APAF1
NM_181861.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0580

Publications

14 publications found

Variant links:

Genes affected

APAF1 (HGNC:576): (apoptotic peptidase activating factor 1) This gene encodes a cytoplasmic protein that initiates apoptosis. This protein contains several copies of the WD-40 domain, a caspase recruitment domain (CARD), and an ATPase domain (NB-ARC). Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves caspase 9 preproprotein, releasing its mature, activated form. Activated caspase 9 stimulates the subsequent caspase cascade that commits the cell to apoptosis. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

APAF1 Gene-Disease associations (from GenCC):

depressive disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

APAF1 links:

Genome browser will be placed here

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=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APAF1	NM_181861.2 link	c.3084+93A>C		intron_variant	Intron 22 of 26	ENST00000551964.6	NP_863651.1	O14727-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APAF1	ENST00000551964.6 link	c.3084+93A>C		intron_variant	Intron 22 of 26	1	NM_181861.2	ENSP00000448165.2		O14727-1

Frequencies

GnomAD3 genomes

AF:

0.0843

AC:

12821

AN:

152100

Hom.:

724

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0175

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.245

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0879

GnomAD4 exome

AF:

0.101

AC:

127932

AN:

1272226

Hom.:

7495

AF XY:

0.104

AC XY:

66865

AN XY:

642624

show subpopulations

African (AFR)

AF:

0.0150

AC:

447

AN:

29724

American (AMR)

AF:

0.117

AC:

5180

AN:

44184

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

2981

AN:

24680

East Asian (EAS)

AF:

0.246

AC:

9420

AN:

38274

South Asian (SAS)

AF:

0.189

AC:

15475

AN:

82012

European-Finnish (FIN)

AF:

0.120

AC:

5659

AN:

47158

Middle Eastern (MID)

AF:

0.136

AC:

724

AN:

5330

European-Non Finnish (NFE)

AF:

0.0872

AC:

82566

AN:

946822

Other (OTH)

AF:

0.101

AC:

5480

AN:

54042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

5406

10812

16219

21625

27031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2952

5904

8856

11808

14760

<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:

0.0841

AC:

12804

AN:

152218

Hom.:

723

Cov.:

AF XY:

0.0889

AC XY:

6619

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0175

AC:

725

AN:

41546

American (AMR)

AF:

0.108

AC:

1655

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

443

AN:

3472

East Asian (EAS)

AF:

0.245

AC:

1264

AN:

5162

South Asian (SAS)

AF:

0.180

AC:

867

AN:

4818

European-Finnish (FIN)

AF:

0.117

AC:

1237

AN:

10598

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0929

AC:

6318

AN:

68004

Other (OTH)

AF:

0.0884

AC:

187

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

556

1111

1667

2222

2778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0961

Hom.:

427

Bravo

AF:

0.0788

Asia WGS

AF:

0.177

AC:

615

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.6

(source)

DANN

Benign

0.64

PhyloP100

0.058

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over