Genetic Variant APEX2:p.Asn89Ser (chrX-55002275-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014481.4(APEX2):c.266A>G(p.Asn89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,202,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

APEX2
NM_014481.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.343

Publications

0 publications found

Variant links:

Genes affected

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

APEX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019601256).

BP6

Variant X-55002275-A-G is Benign according to our data. Variant chrX-55002275-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3413464.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX2	NM_014481.4	MANE Select	c.266A>G	p.Asn89Ser	missense	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-92+646A>G		intron	N/A	NP_001258677.1	B7ZA71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APEX2	ENST00000374987.4	TSL:1 MANE Select	c.266A>G	p.Asn89Ser	missense	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
APEX2	ENST00000919358.1		c.266A>G	p.Asn89Ser	missense	Exon 3 of 6	ENSP00000589417.1
APEX2	ENST00000886736.1		c.266A>G	p.Asn89Ser	missense	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes

AF:

0.0000890

AC:

AN:

112310

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

169154

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000917

AC:

AN:

1090555

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

357537

show subpopulations

African (AFR)

AF:

0.000305

AC:

AN:

26225

American (AMR)

AF:

0.00

AC:

AN:

34130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18803

East Asian (EAS)

AF:

0.00

AC:

AN:

30116

South Asian (SAS)

AF:

0.00

AC:

AN:

52210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

838958

Other (OTH)

AF:

0.0000219

AC:

AN:

45765

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112310

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

34482

show subpopulations

African (AFR)

AF:

0.000292

AC:

AN:

30869

American (AMR)

AF:

0.00

AC:

AN:

10694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

2686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53220

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

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:

0.000142

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.47

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.52

M_CAP

Benign

0.0072

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.7

PhyloP100

0.34

PrimateAI

Benign

0.26

PROVEAN

Benign

0.72

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.016

MVP

0.32

MPC

0.12

ClinPred

0.015

GERP RS

4.4

Varity_R

0.035

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over