12-98726055-T-G

Position:

• chr12-98726055-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181861.2(APAF1):​c.3456+515T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 152,148 control chromosomes in the GnomAD database, including 61,036 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 0.90 (61036 hom., cov: 31)
• Consequence: APAF1 NM_181861.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0340

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APAF1	NM_181861.2	c.3456+515T>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.3456+515T>G		intron_variant		1	NM_181861.2	ENSP00000448165.2

Frequencies

GnomAD3 genomes AF: 0.895 AC: 136087 AN: 152030 Hom.: 60979 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.886

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.876

Gnomad OTH AF: 0.881

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

GnomAD4 genome AF: 0.895 AC: 136206 AN: 152148 Hom.: 61036 Cov.: 31 AF XY: 0.893 AC XY: 66421 AN XY: 74356

Gnomad4 AFR AF: 0.944

Gnomad4 AMR AF: 0.914

Gnomad4 ASJ AF: 0.886

Gnomad4 EAS AF: 0.891

Gnomad4 SAS AF: 0.872

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.876

Gnomad4 OTH AF: 0.881

Alfa AF: 0.869 Hom.: 4258

Bravo AF: 0.902

Asia WGS AF: 0.899 AC: 3127 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.8
DANN	Benign	0.51

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: rs1866477; hg19: chr12-99119833;