12-98659331-G-C

Variant names:

• chr12-98659331-G-C
• rs141157255
• NM_181861.2:c.698G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181861.2(APAF1):​c.698G>C​(p.Arg233Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 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. R233H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APAF1 NM_181861.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892

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.698G>C	p.Arg233Pro	missense	Exon 5 of 27	NP_863651.1	O14727-1
	APAF1	NM_013229.3		c.665G>C	p.Arg222Pro	missense	Exon 5 of 27	NP_037361.1	O14727-2
	APAF1	NM_181868.2		c.698G>C	p.Arg233Pro	missense	Exon 5 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.698G>C	p.Arg233Pro	missense	Exon 5 of 27	ENSP00000448165.2	O14727-1
	APAF1	ENST00000550527.5	TSL:1	c.665G>C	p.Arg222Pro	missense	Exon 4 of 26	ENSP00000448449.1	O14727-2
	APAF1	ENST00000547045.5	TSL:1	c.698G>C	p.Arg233Pro	missense	Exon 4 of 25	ENSP00000449791.1	O14727-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.6
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.88	P
Vest4		0.67
MutPred		0.76		Loss of MoRF binding (P = 0.0039)
MVP		0.86
MPC		0.59
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.91
gMVP		0.81
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs141157255; hg19: chr12-99053109;