rs762384959

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001641.4(APEX1):​c.259G>A​(p.Glu87Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

9
8
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.48
Variant links:
Genes affected
APEX1 (HGNC:587): (apurinic/apyrimidinic endodeoxyribonuclease 1) The APEX gene encodes the major AP endonuclease in human cells. It encodes the APEX endonuclease, a DNA repair enzyme with apurinic/apyrimidinic (AP) activity. Such AP activity sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. The AP sites are the most frequent pre-mutagenic lesions that can prevent normal DNA replication. Splice variants have been found for this gene; all encode the same protein. Disruptions in the biological functions related to APEX are associated with many various malignancies and neurodegenerative diseases.[provided by RefSeq, Dec 2019]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APEX1NM_001641.4 linkc.259G>A p.Glu87Lys missense_variant Exon 4 of 5 ENST00000216714.8 NP_001632.2 P27695Q5TZP7
APEX1NM_001244249.2 linkc.259G>A p.Glu87Lys missense_variant Exon 4 of 5 NP_001231178.1 P27695Q5TZP7
APEX1NM_080648.3 linkc.259G>A p.Glu87Lys missense_variant Exon 4 of 5 NP_542379.1 P27695Q5TZP7
APEX1NM_080649.3 linkc.259G>A p.Glu87Lys missense_variant Exon 4 of 5 NP_542380.1 P27695Q5TZP7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APEX1ENST00000216714.8 linkc.259G>A p.Glu87Lys missense_variant Exon 4 of 5 1 NM_001641.4 ENSP00000216714.3 P27695

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461802
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727214
show subpopulations
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.44
T;T;T;T;T;D;.;D;D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.97
.;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.81
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Uncertain
2.8
M;M;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.015
D;D;T;D;D;D;D;D;D;D
Sift4G
Benign
0.27
T;T;T;D;T;T;D;T;T;T
Polyphen
1.0
D;D;.;.;D;.;.;.;.;.
Vest4
0.83
MutPred
0.58
Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);Gain of catalytic residue at I91 (P = 0.0098);.;.;
MVP
0.97
MPC
0.76
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.96
gMVP
0.91

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: rs762384959; hg19: chr14-20924839; API