14-20456275-T-C

Variant names:

• chr14-20456275-T-C
• rs3136817
• NM_001641.4:c.246+174T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.682
• Publications: 21 publications found

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

ACMG classification

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	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
	APEX1	NM_080648.3		c.246+174T>C		intron	N/A	NP_542379.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34139 AN: 152098 Hom.: 4061 Cov.: 32

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.: 32 AF XY: 0.227 AC XY: 16914 AN XY: 74422

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: 64 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17434 AN: 68014

Other (OTH) AF: 0.241 AC: 508 AN: 2110

Alfa AF: 0.241 Hom.: 6651

Bravo AF: 0.218

Asia WGS AF: 0.134 AC: 468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.54
PhyloP100		-0.68
PromoterAI		0.00040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3136817; hg19: chr14-20924434;