rs3136817

chr14-20456275-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.682

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1274915.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APEX1	NM_001641.4	c.246+174T>C		intron_variant		ENST00000216714.8
APEX1	NM_001244249.2	c.246+174T>C		intron_variant
APEX1	NM_080648.3	c.246+174T>C		intron_variant
APEX1	NM_080649.3	c.246+174T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APEX1	ENST00000216714.8	c.246+174T>C		intron_variant		1	NM_001641.4	P1

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

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.197

Gnomad4 EAS AF: 0.0965

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.330

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.241

Alfa AF: 0.246 Hom.: 4671

Bravo AF: 0.218

Asia WGS AF: 0.134 AC: 468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.1
Dann	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs3136817; hg19: chr14-20924434;