chr12-98698843-A-G

Position:

• chr12-98698843-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.2305-565A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,244 control chromosomes in the GnomAD database, including 1,205 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 0.12 (1205 hom., cov: 32)
• Consequence: APAF1 NM_181861.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.32

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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APAF1	NM_181861.2	c.2305-565A>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.2305-565A>G		intron_variant		1	NM_181861.2	ENSP00000448165.2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18543 AN: 152126 Hom.: 1199 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0932

Gnomad OTH AF: 0.117

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.122 AC: 18566 AN: 152244 Hom.: 1205 Cov.: 32 AF XY: 0.125 AC XY: 9272 AN XY: 74428

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0931

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0934 Hom.: 784

Bravo AF: 0.122

Asia WGS AF: 0.207 AC: 721 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.10
DANN	Benign	0.53

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: rs1007573; hg19: chr12-99092621;