12-98665674-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_181861.2(APAF1):c.1077T>C(p.Tyr359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,613,998 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (136 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (130 hom.)
• Consequence: APAF1 NM_181861.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00400

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 12-98665674-T-C is Benign according to our data. Variant chr12-98665674-T-C is described in ClinVar as [Benign]. Clinvar id is 773029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APAF1	NM_181861.2	c.1077T>C	p.Tyr359=	synonymous_variant	8/27	ENST00000551964.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APAF1	ENST00000551964.6	c.1077T>C	p.Tyr359=	synonymous_variant	8/27	1	NM_181861.2	P1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3668 AN: 152100 Hom.: 136 Cov.: 31

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00636 AC: 1599 AN: 251274 Hom.: 51 AF XY: 0.00466 AC XY: 633 AN XY: 135804

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00250 AC: 3652 AN: 1461780 Hom.: 130 Cov.: 32 AF XY: 0.00217 AC XY: 1581 AN XY: 727194

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.0242 AC: 3677 AN: 152218 Hom.: 136 Cov.: 31 AF XY: 0.0230 AC XY: 1713 AN XY: 74450

Gnomad4 AFR AF: 0.0847

Gnomad4 AMR AF: 0.00759

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0105 Hom.: 22

Bravo AF: 0.0281

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

APAF1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.5
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs57171247; hg19: chr12-99059452;