12-98726055-T-G

Variant names:

• chr12-98726055-T-G
• rs1866477
• NM_181861.2:c.3456+515T>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.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
• Publications: 7 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	NM_181861.2	MANE Select	c.3456+515T>G		intron	N/A	NP_863651.1
	APAF1	NM_013229.3		c.3423+515T>G		intron	N/A	NP_037361.1
	APAF1	NM_181868.2		c.3327+515T>G		intron	N/A	NP_863658.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.3456+515T>G		intron	N/A	ENSP00000448165.2
	APAF1	ENST00000550527.5	TSL:1	c.3423+515T>G		intron	N/A	ENSP00000448449.1
	APAF1	ENST00000547045.5	TSL:1	c.3327+515T>G		intron	N/A	ENSP00000449791.1

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

African (AFR) AF: 0.944 AC: 39185 AN: 41516

American (AMR) AF: 0.914 AC: 13973 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.886 AC: 3077 AN: 3472

East Asian (EAS) AF: 0.891 AC: 4611 AN: 5176

South Asian (SAS) AF: 0.872 AC: 4198 AN: 4814

European-Finnish (FIN) AF: 0.826 AC: 8727 AN: 10566

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.876 AC: 59560 AN: 68000

Other (OTH) AF: 0.881 AC: 1862 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.8
DANN	Benign	0.51
PhyloP100		-0.034
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: rs1866477; hg19: chr12-99119833;