chr11-43335908-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001142930.2(API5):​c.1406C>G​(p.Ser469Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

API5
NM_001142930.2 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60
Variant links:
Genes affected
API5 (HGNC:594): (apoptosis inhibitor 5) This gene encodes an apoptosis inhibitory protein whose expression prevents apoptosis after growth factor deprivation. This protein suppresses the transcription factor E2F1-induced apoptosis and also interacts with, and negatively regulates Acinus, a nuclear factor involved in apoptotic DNA fragmentation. Its depletion enhances the cytotoxic action of the chemotherapeutic drugs. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity API5_HUMAN
BP4
Computational evidence support a benign effect (MetaRNN=0.1976566).
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
API5NM_001142930.2 linkc.1406C>G p.Ser469Cys missense_variant Exon 13 of 14 ENST00000531273.6 NP_001136402.1 Q9BZZ5-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
API5ENST00000531273.6 linkc.1406C>G p.Ser469Cys missense_variant Exon 13 of 14 2 NM_001142930.2 ENSP00000431391.1 Q9BZZ5-4

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250596
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135426
show subpopulations
Gnomad AFR exome
AF:
0.0000616
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:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461456
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727014
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
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:
0.0000331
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000453

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 26, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1406C>G (p.S469C) alteration is located in exon 13 (coding exon 13) of the API5 gene. This alteration results from a C to G substitution at nucleotide position 1406, causing the serine (S) at amino acid position 469 to be replaced by a cysteine (C). 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
0.089
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.49
CADD
Uncertain
25
DANN
Benign
0.95
DEOGEN2
Benign
0.057
.;T;.;.;.;T
Eigen
Benign
0.14
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.20
T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
0.69
.;N;.;N;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-2.0
N;N;N;N;N;N
REVEL
Benign
0.057
Sift
Benign
0.093
T;T;T;T;T;T
Sift4G
Uncertain
0.053
T;T;T;T;T;T
Polyphen
0.51, 0.25
.;P;.;B;B;.
Vest4
0.18
MutPred
0.41
.;Loss of phosphorylation at S469 (P = 0.0061);.;Loss of phosphorylation at S469 (P = 0.0061);Loss of phosphorylation at S469 (P = 0.0061);.;
MVP
0.36
MPC
1.3
ClinPred
0.25
T
GERP RS
5.2
Varity_R
0.11
gMVP
0.67

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

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

Other links and lift over

dbSNP: rs994088627; hg19: chr11-43357458; API