rs2278361

Positions:

• chr12-98649429-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APAF1	NM_181861.2	c.329-58A>G		intron_variant		ENST00000551964.6	NP_863651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APAF1	ENST00000551964.6	c.329-58A>G		intron_variant		1	NM_181861.2	ENSP00000448165	P1

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

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.153

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.209

Gnomad4 OTH exome AF: 0.184

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

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.180

Alfa AF: 0.194 Hom.: 1446

Bravo AF: 0.190

Asia WGS AF: 0.122 AC: 425 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2278361; hg19: chr12-99043207;