chrX-55002430-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_014481.4(APEX2):c.421C>G(p.Arg141Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,182,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R141H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000012 ( 0 hom. 3 hem. )

Consequence

APEX2
NM_014481.4 missense, splice_region

Scores

Splicing: ADA: 0.0005303

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.937

Publications

4 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30498397).

BS2

High Hemizygotes in GnomAdExome4 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.421C>G	p.Arg141Gly	missense splice_region	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-91-532C>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.421C>G	p.Arg141Gly	missense splice_region	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
APEX2	ENST00000919358.1		c.421C>G	p.Arg141Gly	missense splice_region	Exon 3 of 6	ENSP00000589417.1
APEX2	ENST00000886736.1		c.421C>G	p.Arg141Gly	missense splice_region	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

149892

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1069190

Hom.:

Cov.:

AF XY:

0.00000873

AC XY:

AN XY:

343794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25492

American (AMR)

AF:

0.00

AC:

AN:

30037

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17233

East Asian (EAS)

AF:

0.00

AC:

AN:

29798

South Asian (SAS)

AF:

0.00

AC:

AN:

48320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39541

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3957

European-Non Finnish (NFE)

AF:

0.0000157

AC:

AN:

829920

Other (OTH)

AF:

0.00

AC:

AN:

44892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.0000177

AC:

AN:

112856

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34992

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31050

American (AMR)

AF:

0.00

AC:

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6263

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53319

Other (OTH)

AF:

0.00

AC:

AN:

1528

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

314

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0049

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.3

PhyloP100

0.94

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.33

Sift

Benign

0.27

Sift4G

Benign

0.21

Polyphen

0.68

Vest4

0.30

MutPred

0.57

Loss of MoRF binding (P = 0.0101)

MVP

0.64

MPC

0.47

ClinPred

0.64

GERP RS

-0.65

Varity_R

0.21

gMVP

0.85

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00053

dbscSNV1_RF

Benign

0.092

SpliceAI score (max)

0.090

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over