chr14-20456789-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001641.4(APEX1):​c.368C>T​(p.Ser123Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61
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. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.36747116).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
APEX1NM_001641.4 linkuse as main transcriptc.368C>T p.Ser123Leu missense_variant 4/5 ENST00000216714.8
APEX1NM_001244249.2 linkuse as main transcriptc.368C>T p.Ser123Leu missense_variant 4/5
APEX1NM_080648.3 linkuse as main transcriptc.368C>T p.Ser123Leu missense_variant 4/5
APEX1NM_080649.3 linkuse as main transcriptc.368C>T p.Ser123Leu missense_variant 4/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
APEX1ENST00000216714.8 linkuse as main transcriptc.368C>T p.Ser123Leu missense_variant 4/51 NM_001641.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00000796
AC:
2
AN:
251378
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
0.00000547
AC:
8
AN:
1461886
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00000756

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 submitterclinical testingAmbry GeneticsAug 16, 2021The c.368C>T (p.S123L) alteration is located in exon 4 (coding exon 3) of the APEX1 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the serine (S) at amino acid position 123 to be replaced by a leucine (L). 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
0.11
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;T;T;T;T;.;T;T;.
Eigen
Benign
0.12
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.88
.;.;D;D;D;D;D;D;D
M_CAP
Uncertain
0.097
D
MetaRNN
Benign
0.37
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.4
L;L;.;.;L;.;.;.;.
MutationTaster
Benign
0.99
D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.20
T;T;D;T;T;T;T;T;T
Sift4G
Uncertain
0.037
D;D;D;T;D;T;T;T;T
Polyphen
0.74
P;P;.;.;P;.;.;.;.
Vest4
0.31
MutPred
0.50
Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);Gain of catalytic residue at P122 (P = 5e-04);.;.;
MVP
0.89
MPC
0.17
ClinPred
0.23
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.38
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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: rs1268308753; hg19: chr14-20924948; API