dbSNP rs3136817: APEX1:c.246+174T>C (chr14-20456275-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001641.4(APEX1):c.246+174T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,216 control chromosomes in the GnomAD database, including 4,067 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4067 hom., cov: 32)

Consequence

APEX1
NM_001641.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.682

Publications

21 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 (BayesDel_noAF=-0.81).

BP6

Variant 14-20456275-T-C is Benign according to our data. Variant chr14-20456275-T-C is described in ClinVar as Benign. ClinVar VariationId is 1274915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
APEX1	NM_001641.4	MANE Select	c.246+174T>C	intron	N/A	NP_001632.2
APEX1	NM_001244249.2		c.246+174T>C	intron	N/A	NP_001231178.1	Q5TZP7
APEX1	NM_080648.3		c.246+174T>C	intron	N/A	NP_542379.1	Q5TZP7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APEX1	ENST00000216714.8	TSL:1 MANE Select	c.246+174T>C	intron	N/A	ENSP00000216714.3	P27695
APEX1	ENST00000398030.8	TSL:1	c.246+174T>C	intron	N/A	ENSP00000381111.4	P27695
APEX1	ENST00000555414.5	TSL:1	c.246+174T>C	intron	N/A	ENSP00000451979.1	P27695

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

34139

AN:

152098

Hom.:

4061

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.249

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.0965

Gnomad SAS

AF:

0.123

Gnomad FIN

AF:

0.330

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.256

Gnomad OTH

AF:

0.239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.225

AC:

34188

AN:

152216

Hom.:

4067

Cov.:

AF XY:

0.227

AC XY:

16914

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.166

AC:

6893

AN:

41532

American (AMR)

AF:

0.250

AC:

3819

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

682

AN:

3468

East Asian (EAS)

AF:

0.0965

AC:

501

AN:

5192

South Asian (SAS)

AF:

0.124

AC:

597

AN:

4830

European-Finnish (FIN)

AF:

0.330

AC:

3484

AN:

10572

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.256

AC:

17434

AN:

68014

Other (OTH)

AF:

0.241

AC:

508

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1382

2764

4147

5529

6911

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.241

Hom.:

6651

Bravo

AF:

0.218

Asia WGS

AF:

0.134

AC:

468

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.1

(source)

DANN

Benign

0.54

PhyloP100

-0.68

PromoterAI

0.00040

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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