Genetic Variant APAF1:p.Ser31Thr (chr12-98648451-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181861.2(APAF1):c.92G>C(p.Ser31Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

APAF1
NM_181861.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.10

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15656671).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APAF1	NM_181861.2 link	c.92G>C	p.Ser31Thr	missense_variant	Exon 2 of 27	ENST00000551964.6	NP_863651.1	O14727-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APAF1	ENST00000551964.6 link	c.92G>C	p.Ser31Thr	missense_variant	Exon 2 of 27	1	NM_181861.2	ENSP00000448165.2		O14727-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251356

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461326

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727022

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92G>C (p.S31T) alteration is located in exon 2 (coding exon 1) of the APAF1 gene. This alteration results from a G to C substitution at nucleotide position 92, causing the serine (S) at amino acid position 31 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.25

T;.;.;.;T;.;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

T;T;T;T;T;.;T;.;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;M;M;M;.;M;M;M;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D;D;D

Polyphen

0.0

B;B;B;B;.;B;B;B;.

Vest4

0.14

MutPred

0.52

Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);Gain of catalytic residue at D27 (P = 0);

MVP

0.55

MPC

0.24

ClinPred

0.16

GERP RS

1.9

Varity_R

0.32

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over