12-98648396-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181861.2(APAF1):c.37A>G(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: APAF1 NM_181861.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.28

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27527693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APAF1	NM_181861.2	c.37A>G	p.Arg13Gly	missense_variant	2/27	ENST00000551964.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APAF1	ENST00000551964.6	c.37A>G	p.Arg13Gly	missense_variant	2/27	1	NM_181861.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251348 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135844

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461764 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727188

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.37A>G (p.R13G) alteration is located in exon 2 (coding exon 1) of the APAF1 gene. This alteration results from a A to G substitution at nucleotide position 37, causing the arginine (R) at amino acid position 13 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;.;T;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;T;T;T;T;.;T;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;M;M;M;.;M;M;M;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D
Polyphen		0.87	P;D;P;P;.;D;P;P;.
Vest4		0.25
MutPred		0.67		Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);Gain of catalytic residue at L9 (P = 0.0014);
MVP		0.72
MPC		0.50
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.84
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs966090697; hg19: chr12-99042174;