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rs1130409

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001641.4(APEX1):c.444T>A(p.Asp148Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

1
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.117
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.099983275).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APEX1NM_001641.4 linkuse as main transcriptc.444T>A p.Asp148Glu missense_variant 5/5 ENST00000216714.8
APEX1NM_001244249.2 linkuse as main transcriptc.444T>A p.Asp148Glu missense_variant 5/5
APEX1NM_080648.3 linkuse as main transcriptc.444T>A p.Asp148Glu missense_variant 5/5
APEX1NM_080649.3 linkuse as main transcriptc.444T>A p.Asp148Glu missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APEX1ENST00000216714.8 linkuse as main transcriptc.444T>A p.Asp148Glu missense_variant 5/51 NM_001641.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248646
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134488
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460840
Hom.:
0
Cov.:
55
AF XY:
0.00
AC XY:
0
AN XY:
726656
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.050
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
Cadd
Benign
2.2
Dann
Benign
0.70
DEOGEN2
Benign
0.16
T;T;T;T;T;T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.45
N
M_CAP
Benign
0.069
D
MetaRNN
Benign
0.10
T;T;T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.63
N;N;.;N;.;.;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.20
N;N;N;N;N;N;N
REVEL
Benign
0.19
Sift
Benign
1.0
T;T;T;T;T;T;T
Sift4G
Benign
1.0
T;T;T;T;T;T;T
Polyphen
0.0
B;B;.;B;.;.;.
Vest4
0.025
MutPred
0.29
Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);.;.;
MVP
0.70
MPC
0.16
ClinPred
0.027
T
GERP RS
-2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.23
gMVP
0.36

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: rs1130409; hg19: chr14-20925154; API