dbSNP rs2307486: APEX1:p.Ile64Val (chr14-20456045-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

Publications

39 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 417 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APEX1	NM_001641.4	MANE Select	c.190A>G	p.Ile64Val	missense	Exon 3 of 5	NP_001632.2
APEX1	NM_001244249.2		c.190A>G	p.Ile64Val	missense	Exon 3 of 5	NP_001231178.1	Q5TZP7
APEX1	NM_080648.3		c.190A>G	p.Ile64Val	missense	Exon 3 of 5	NP_542379.1	Q5TZP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APEX1	ENST00000216714.8	TSL:1 MANE Select	c.190A>G	p.Ile64Val	missense	Exon 3 of 5	ENSP00000216714.3	P27695
APEX1	ENST00000398030.8	TSL:1	c.190A>G	p.Ile64Val	missense	Exon 3 of 5	ENSP00000381111.4	P27695
APEX1	ENST00000555414.5	TSL:1	c.190A>G	p.Ile64Val	missense	Exon 3 of 5	ENSP00000451979.1	P27695

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

GnomAD2 exomes

AF:

0.00741

AC:

1863

AN:

251488

AF XY:

0.00633

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 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

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0218

AC:

976

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0505

AC:

2005

AN:

39700

South Asian (SAS)

AF:

0.000615

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1112012

Other (OTH)

AF:

0.00184

AC:

111

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

208

417

625

834

1042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00274

AC:

417

AN:

152282

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

224

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41564

American (AMR)

AF:

0.00739

AC:

113

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0510

AC:

264

AN:

5178

South Asian (SAS)

AF:

0.000623

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00213

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0065

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

PhyloP100

6.8

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.83

REVEL

Benign

0.12

Sift

Benign

0.075

Sift4G

Benign

0.13

Polyphen

0.23

Vest4

0.11

MVP

0.79

MPC

0.15

ClinPred

0.039

GERP RS

5.8

PromoterAI

-0.0015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.51

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over