11-43335890-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001142930.2(API5):​c.1388G>A​(p.Gly463Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.000021 ( 0 hom. )

Consequence

API5
NM_001142930.2 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03189209).
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.1388G>A p.Gly463Asp 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.1388G>A p.Gly463Asp missense_variant Exon 13 of 14 2 NM_001142930.2 ENSP00000431391.1 Q9BZZ5-4

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00115
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000641
AC:
16
AN:
249642
Hom.:
0
AF XY:
0.0000741
AC XY:
10
AN XY:
134906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000764
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1460554
Hom.:
0
Cov.:
30
AF XY:
0.0000179
AC XY:
13
AN XY:
726510
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000605
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00116
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378
ExAC
AF:
0.0000988
AC:
12
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1388G>A (p.G463D) alteration is located in exon 13 (coding exon 13) of the API5 gene. This alteration results from a G to A substitution at nucleotide position 1388, causing the glycine (G) at amino acid position 463 to be replaced by an aspartic acid (D). 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
-0.45
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
21
DANN
Benign
0.93
DEOGEN2
Benign
0.032
.;T;.;.;.;T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.050
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.83
T;T;T;T;T;T
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.032
T;T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
1.1
.;L;.;L;.;.
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.35
N;N;N;N;N;N
REVEL
Benign
0.018
Sift
Benign
0.49
T;T;T;T;T;T
Sift4G
Benign
0.71
T;T;T;T;T;T
Polyphen
0.55, 0.14, 0.28
.;P;.;B;B;.
Vest4
0.16
MutPred
0.28
.;Loss of glycosylation at S462 (P = 0.0422);.;Loss of glycosylation at S462 (P = 0.0422);Loss of glycosylation at S462 (P = 0.0422);.;
MVP
0.33
MPC
0.95
ClinPred
0.081
T
GERP RS
4.2
Varity_R
0.045
gMVP
0.57

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: rs768894583; hg19: chr11-43357440; API