chr12-98662517-T-C

Variant names:

• chr12-98662517-T-C
• rs746875464
• NM_181861.2:c.772T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_181861.2(APAF1):​c.772T>C​(p.Cys258Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C258S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: APAF1 NM_181861.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 3 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: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.772T>C	p.Cys258Arg	missense	Exon 6 of 27	NP_863651.1	O14727-1
	APAF1	NM_013229.3		c.739T>C	p.Cys247Arg	missense	Exon 6 of 27	NP_037361.1	O14727-2
	APAF1	NM_181868.2		c.772T>C	p.Cys258Arg	missense	Exon 6 of 26	NP_863658.1	O14727-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APAF1	ENST00000551964.6	TSL:1 MANE Select	c.772T>C	p.Cys258Arg	missense	Exon 6 of 27	ENSP00000448165.2	O14727-1
	APAF1	ENST00000550527.5	TSL:1	c.739T>C	p.Cys247Arg	missense	Exon 5 of 26	ENSP00000448449.1	O14727-2
	APAF1	ENST00000547045.5	TSL:1	c.772T>C	p.Cys258Arg	missense	Exon 5 of 25	ENSP00000449791.1	O14727-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461428 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727044

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111760

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.63
MutPred		0.70		Gain of catalytic residue at A253 (P = 0.0185)
MVP		0.93
MPC		1.2
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.88
gMVP		0.91
Mutation Taster		=63/37	polymorphism

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: rs746875464; hg19: chr12-99056295;