chr14-20456008-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001641.4(APEX1):c.153G>C(p.Gln51His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,614,190 control chromosomes in the GnomAD database, including 1,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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: 𝑓 0.024 ( 55 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1007 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.37

Publications

52 publications found

Variant links:

COSMIC-nc: COSV105067964

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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004014522).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0237 (3605/152314) while in subpopulation NFE AF = 0.0399 (2716/68034). AF 95% confidence interval is 0.0387. There are 55 homozygotes in GnomAd4. There are 1637 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3605 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4 link	c.153G>C	p.Gln51His	missense_variant	Exon 3 of 5	ENST00000216714.8	NP_001632.2	P27695Q5TZP7
APEX1	NM_001244249.2 link	c.153G>C	p.Gln51His	missense_variant	Exon 3 of 5		NP_001231178.1	P27695Q5TZP7
APEX1	NM_080648.3 link	c.153G>C	p.Gln51His	missense_variant	Exon 3 of 5		NP_542379.1	P27695Q5TZP7
APEX1	NM_080649.3 link	c.153G>C	p.Gln51His	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.153G>C	p.Gln51His	missense_variant	Exon 3 of 5	1	NM_001641.4	ENSP00000216714.3		P27695

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3604

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00760

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0399

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0209

AC:

5263

AN:

251436

AF XY:

0.0210

show subpopulations

Gnomad AFR exome

AF:

0.00609

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.00694

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0100

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0221

GnomAD4 exome

AF:

0.0344

AC:

50306

AN:

1461876

Hom.:

1007

Cov.:

AF XY:

0.0333

AC XY:

24243

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00511

AC:

171

AN:

33478

American (AMR)

AF:

0.0141

AC:

630

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

203

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00424

AC:

366

AN:

86256

European-Finnish (FIN)

AF:

0.0118

AC:

630

AN:

53418

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0418

AC:

46472

AN:

1112004

Other (OTH)

AF:

0.0292

AC:

1763

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3152

6305

9457

12610

15762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1728

3456

5184

6912

8640

<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

AF:

0.0237

AC:

3605

AN:

152314

Hom.:

Cov.:

AF XY:

0.0220

AC XY:

1637

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00758

AC:

315

AN:

41568

American (AMR)

AF:

0.0218

AC:

333

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00331

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0399

AC:

2716

AN:

68034

Other (OTH)

AF:

0.0284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

188

375

563

750

938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0347

Hom.:

Bravo

AF:

0.0241

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0376

AC:

323

ExAC

AF:

0.0205

AC:

2493

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0380

EpiControl

AF:

0.0387

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

.;.;D;D;D;D;D;T;D;D;D

MetaRNN

Benign

0.0040

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

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

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

PhyloP100

1.4

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.55

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

REVEL

Benign

0.054

Sift

Uncertain

0.026

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

Sift4G

Benign

0.074

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

Polyphen

0.14

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

Vest4

0.038

MutPred

0.20

Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);.;Gain of catalytic residue at P48 (P = 0.0016);.;.;

MPC

0.17

ClinPred

0.013

GERP RS

5.2

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.55

Mutation Taster

=98/2

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over