12-98648780-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_181861.2(APAF1):c.293G>A(p.Ser98Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: APAF1 NM_181861.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-98648780-G-A is Benign according to our data. Variant chr12-98648780-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2310576.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APAF1	NM_181861.2	c.293G>A	p.Ser98Asn	missense_variant	3/27	ENST00000551964.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APAF1	ENST00000551964.6	c.293G>A	p.Ser98Asn	missense_variant	3/27	1	NM_181861.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461708 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Benign	0.62
DEOGEN2	Benign	0.33	T;.;.;.;T;.;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.72	T;T;T;T;T;.;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.077	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.17	N;N;N;N;.;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.48	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.88	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;B;B;.
Vest4		0.089
MutPred		0.30		Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);Gain of catalytic residue at S95 (P = 0.0019);
MVP		0.68
MPC		0.23
ClinPred		0.044	T
GERP RS		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 2
DS_DL_spliceai		0.28		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-99042558;