rs2307486

Positions:

chr14-20456045-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001641.4(APEX1):c.190A>G(p.Ile64Val) variant causes a missense change. The variant allele was found at a frequency of 0.0023 in 1,614,166 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts 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 0.0027 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 63 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.85

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=0.006541252).

BP6

Variant 14-20456045-A-G is Benign according to our data. Variant chr14-20456045-A-G is described in ClinVar as [Benign]. Clinvar id is 771467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00274 (417/152282) while in subpopulation EAS AF= 0.051 (264/5178). AF 95% confidence interval is 0.0459. There are 7 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
APEX1	NM_001641.4 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant	3/5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant	3/5		NP_001231178.1
APEX1	NM_080648.3 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant	3/5		NP_542379.1
APEX1	NM_080649.3 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant	3/5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8 linkuse as main transcript	c.190A>G	p.Ile64Val	missense_variant	3/5	1	NM_001641.4	ENSP00000216714	P1

Frequencies

GnomAD3 genomes

AF:

0.00275

AC:

418

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00740

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0511

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00741

AC:

1863

AN:

251488

Hom.:

AF XY:

0.00633

AC XY:

860

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0516

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00226

AC:

3298

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1526

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0218

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0505

Gnomad4 SAS exome

AF:

0.000615

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00274

AC:

417

AN:

152282

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0510

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00394

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00649

AC:

788

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

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

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.0065

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

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

REVEL

Benign

0.12

Sift

Benign

0.075

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

Sift4G

Benign

0.13

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

Polyphen

0.23

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

Vest4

0.11

MVP

0.79

MPC

0.15

ClinPred

0.039

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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