chr12-98732429-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_181861.2(APAF1):c.3610G>A(p.Val1204Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,613,344 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: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
APAF1
NM_181861.2 missense
NM_181861.2 missense
Scores
1
6
9
Clinical Significance
Conservation
PhyloP100: 5.84
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]
ANKS1B (HGNC:24600): (ankyrin repeat and sterile alpha motif domain containing 1B) This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease. Expression of this gene has been shown to be elevated in patients with pre-B cell acute lymphocytic leukemia associated with t(1;19) translocation. Alternatively spliced transcript variants encoding different isoforms (some with different subcellular localization, PMID:15004329) have been described for this gene. [provided by RefSeq, Aug 2011]
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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=0.21783641).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APAF1 | NM_181861.2 | c.3610G>A | p.Val1204Ile | missense_variant | 27/27 | ENST00000551964.6 | NP_863651.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APAF1 | ENST00000551964.6 | c.3610G>A | p.Val1204Ile | missense_variant | 27/27 | 1 | NM_181861.2 | ENSP00000448165 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251374Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135854
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461192Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726970
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74318
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.3610G>A (p.V1204I) alteration is located in exon 27 (coding exon 26) of the APAF1 gene. This alteration results from a G to A substitution at nucleotide position 3610, causing the valine (V) at amino acid position 1204 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;.
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;N;N
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Gain of catalytic residue at W325 (P = 1e-04);Gain of catalytic residue at W325 (P = 1e-04);
MVP
ClinPred
D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at