NM_181861.2:c.3084+93A>C

Variant names:

• chr12-98715645-A-C
• rs2288713
• NM_181861.2:c.3084+93A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• Publications: 14 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181861.2. 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
	APAF1	NM_181861.2	MANE Select	c.3084+93A>C		intron	N/A	NP_863651.1	O14727-1
	APAF1	NM_013229.3		c.3051+93A>C		intron	N/A	NP_037361.1	O14727-2
	APAF1	NM_181868.2		c.2955+93A>C		intron	N/A	NP_863658.1	O14727-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.3084+93A>C		intron	N/A	ENSP00000448165.2	O14727-1
	APAF1	ENST00000550527.5	TSL:1	c.3051+93A>C		intron	N/A	ENSP00000448449.1	O14727-2
	APAF1	ENST00000547045.5	TSL:1	c.2955+93A>C		intron	N/A	ENSP00000449791.1	O14727-4

Frequencies

GnomAD3 genomes AF: 0.0843 AC: 12821 AN: 152100 Hom.: 724 Cov.: 31

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

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

GnomAD4 genome AF: 0.0841 AC: 12804 AN: 152218 Hom.: 723 Cov.: 31 AF XY: 0.0889 AC XY: 6619 AN XY: 74418

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: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0929 AC: 6318 AN: 68004

Other (OTH) AF: 0.0884 AC: 187 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		0.058
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288713; hg19: chr12-99109423; COSMIC: COSV107383485; COSMIC: COSV107383485;