Genetic Variant APEX1:p.Ile64Thr (chr14-20456046-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001641.4(APEX1):c.191T>C(p.Ile64Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I64V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APEX1
NM_001641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.55

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 3 of 5	ENST00000216714.8	NP_001632.2	P27695Q5TZP7
APEX1	NM_001244249.2 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 3 of 5		NP_001231178.1	P27695Q5TZP7
APEX1	NM_080648.3 link	c.191T>C	p.Ile64Thr	missense_variant	Exon 3 of 5		NP_542379.1	P27695Q5TZP7
APEX1	NM_080649.3 link	c.191T>C	p.Ile64Thr	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.191T>C	p.Ile64Thr	missense_variant	Exon 3 of 5	1	NM_001641.4	ENSP00000216714.3		P27695

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

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:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

.;.;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.6

M;M;.;.;M;.;.;.;.;.

PhyloP100

7.6

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;.;.;D;.;.;.;.;.

Vest4

0.85

MutPred

0.70

Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);Gain of catalytic residue at K63 (P = 0.0032);.;.;

MVP

0.90

MPC

0.70

ClinPred

1.0

GERP RS

5.8

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.98

gMVP

0.89

Mutation Taster

=9/91

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over