Genetic Variant APEX1:p.Gly39Glu (chr14-20455971-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001641.4(APEX1):c.116G>A(p.Gly39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.58

Publications

6 publications found

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]

APEX1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

APEX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31138664).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5	ENST00000216714.8	NP_001632.2	P27695Q5TZP7
APEX1	NM_001244249.2 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_001231178.1	P27695Q5TZP7
APEX1	NM_080648.3 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_542379.1	P27695Q5TZP7
APEX1	NM_080649.3 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_542380.1	P27695Q5TZP7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8 link	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5	1	NM_001641.4	ENSP00000216714.3		P27695

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

T;T;T;T;T;T;.;T;T;T;.

Eigen

Benign

-0.032

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.83

.;.;T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.1

L;L;.;.;L;.;.;.;.;.;.

PhyloP100

3.6

PrimateAI

Benign

0.39

PROVEAN

Benign

0.89

N;N;N;N;N;N;N;D;N;N;N

REVEL

Benign

0.097

Sift

Benign

0.078

T;T;D;D;T;D;T;D;D;D;D

Sift4G

Benign

0.45

T;T;T;T;T;T;T;D;T;T;T

Polyphen

0.0040

B;B;.;.;B;.;.;.;.;.;.

Vest4

0.36

MutPred

0.17

Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);.;Loss of ubiquitination at K35 (P = 0.0353);.;.;

MVP

0.88

MPC

0.28

ClinPred

0.75

GERP RS

5.2

PromoterAI

-0.0011

Neutral

(source)

Varity_R

0.13

gMVP

0.48

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over