14-20456995-T-G

Position:

chr14-20456995-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000216714.8(APEX1):c.444T>G(p.Asp148Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,612,734 control chromosomes in the GnomAD database, including 169,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.43 ( 14357 hom., cov: 33)

Exomes 𝑓: 0.45 ( 154736 hom. )

Consequence

APEX1
ENST00000216714.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

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]

APEX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4034252E-4).

BP6

Variant 14-20456995-T-G is Benign according to our data. Variant chr14-20456995-T-G is described in ClinVar as [Benign]. Clinvar id is 1297236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
APEX1	NM_001641.4 linkuse as main transcript	c.444T>G	p.Asp148Glu	missense_variant	5/5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2 linkuse as main transcript	c.444T>G	p.Asp148Glu	missense_variant	5/5		NP_001231178.1
APEX1	NM_080648.3 linkuse as main transcript	c.444T>G	p.Asp148Glu	missense_variant	5/5		NP_542379.1
APEX1	NM_080649.3 linkuse as main transcript	c.444T>G	p.Asp148Glu	missense_variant	5/5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8 linkuse as main transcript	c.444T>G	p.Asp148Glu	missense_variant	5/5	1	NM_001641.4	ENSP00000216714	P1

Frequencies

GnomAD3 genomes

AF:

0.428

AC:

65059

AN:

151990

Hom.:

14342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.392

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.480

Gnomad OTH

AF:

0.436

GnomAD3 exomes

AF:

0.421

AC:

104602

AN:

248646

Hom.:

22885

AF XY:

0.415

AC XY:

55788

AN XY:

134488

show subpopulations

Gnomad AFR exome

AF:

0.360

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.359

Gnomad EAS exome

AF:

0.399

Gnomad SAS exome

AF:

0.237

Gnomad FIN exome

AF:

0.522

Gnomad NFE exome

AF:

0.480

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.455

AC:

664499

AN:

1460626

Hom.:

154736

Cov.:

AF XY:

0.449

AC XY:

325960

AN XY:

726542

show subpopulations

Gnomad4 AFR exome

AF:

0.358

Gnomad4 AMR exome

AF:

0.386

Gnomad4 ASJ exome

AF:

0.357

Gnomad4 EAS exome

AF:

0.396

Gnomad4 SAS exome

AF:

0.241

Gnomad4 FIN exome

AF:

0.515

Gnomad4 NFE exome

AF:

0.480

Gnomad4 OTH exome

AF:

0.434

GnomAD4 genome

AF:

0.428

AC:

65134

AN:

152108

Hom.:

14357

Cov.:

AF XY:

0.428

AC XY:

31844

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.357

Gnomad4 AMR

AF:

0.413

Gnomad4 ASJ

AF:

0.359

Gnomad4 EAS

AF:

0.393

Gnomad4 SAS

AF:

0.240

Gnomad4 FIN

AF:

0.524

Gnomad4 NFE

AF:

0.480

Gnomad4 OTH

AF:

0.436

Alfa

AF:

0.459

Hom.:

32318

Bravo

AF:

0.423

TwinsUK

AF:

0.496

AC:

1838

ALSPAC

AF:

0.470

AC:

1813

ESP6500AA

AF:

0.366

AC:

1611

ESP6500EA

AF:

0.471

AC:

4054

ExAC

AF:

0.420

AC:

50974

Asia WGS

AF:

0.305

AC:

1064

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 24892639, 24076439, 23038158, 20530453, 21198260, 16621887, 17028303, 22466227, 23369758, 22184996, 22224629, 22193858, 18823566, 21538578, 19762350, 11024165, 19041121, 10371543, 23776569, 27050370, 24310503, 24523018, 26257461) -

APEX1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

2.4

DANN

Benign

0.66

DEOGEN2

Benign

0.16

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.59

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

MetaRNN

Benign

0.00034

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

N;N;.;N;.;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.20

N;N;N;N;N;N;N

REVEL

Benign

0.20

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);.;.;

MPC

0.16

ClinPred

0.0026

GERP RS

-2.6

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over