NM_181861.2:c.329-58A>G

Variant names:

• chr12-98649429-A-G
• rs2278361
• NM_181861.2:c.329-58A>G

Variant summary

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

The NM_181861.2(APAF1):​c.329-58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,563,344 control chromosomes in the GnomAD database, including 32,518 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 (2967 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29551 hom.)
• Consequence: APAF1 NM_181861.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246
• Publications: 16 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 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.329-58A>G		intron	N/A	NP_863651.1
	APAF1	NM_013229.3		c.296-58A>G		intron	N/A	NP_037361.1
	APAF1	NM_181868.2		c.329-58A>G		intron	N/A	NP_863658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.329-58A>G		intron	N/A	ENSP00000448165.2
	APAF1	ENST00000550527.5	TSL:1	c.296-58A>G		intron	N/A	ENSP00000448449.1
	APAF1	ENST00000547045.5	TSL:1	c.329-58A>G		intron	N/A	ENSP00000449791.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29172 AN: 152050 Hom.: 2962 Cov.: 33

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.201 AC: 283360 AN: 1411176 Hom.: 29551 AF XY: 0.197 AC XY: 139040 AN XY: 704632

African (AFR) AF: 0.180 AC: 5843 AN: 32438

American (AMR) AF: 0.237 AC: 10485 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3256 AN: 25784

East Asian (EAS) AF: 0.153 AC: 6014 AN: 39378

South Asian (SAS) AF: 0.121 AC: 10288 AN: 84798

European-Finnish (FIN) AF: 0.249 AC: 13277 AN: 53232

Middle Eastern (MID) AF: 0.115 AC: 649 AN: 5638

European-Non Finnish (NFE) AF: 0.209 AC: 222774 AN: 1067038

Other (OTH) AF: 0.184 AC: 10774 AN: 58628

GnomAD4 genome AF: 0.192 AC: 29191 AN: 152168 Hom.: 2967 Cov.: 33 AF XY: 0.191 AC XY: 14223 AN XY: 74386

African (AFR) AF: 0.180 AC: 7489 AN: 41532

American (AMR) AF: 0.196 AC: 3000 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.128 AC: 661 AN: 5178

South Asian (SAS) AF: 0.117 AC: 564 AN: 4824

European-Finnish (FIN) AF: 0.247 AC: 2616 AN: 10574

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13831 AN: 67992

Other (OTH) AF: 0.180 AC: 381 AN: 2112

Alfa AF: 0.193 Hom.: 2083

Bravo AF: 0.190

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2278361; hg19: chr12-99043207;