14-20457510-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001641.4(APEX1):c.*2A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00473 in 1,613,578 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: APEX1 NM_001641.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-20457510-A-T is Benign according to our data. Variant chr14-20457510-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2644051.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APEX1	NM_001641.4	c.*2A>T		3_prime_UTR_variant	5/5	ENST00000216714.8
APEX1	NM_001244249.2	c.*2A>T		3_prime_UTR_variant	5/5
APEX1	NM_080648.3	c.*2A>T		3_prime_UTR_variant	5/5
APEX1	NM_080649.3	c.*2A>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APEX1	ENST00000216714.8	c.*2A>T		3_prime_UTR_variant	5/5	1	NM_001641.4	P1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00336 AC: 844 AN: 250868 Hom.: 4 AF XY: 0.00365 AC XY: 495 AN XY: 135666

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.00532

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00487 AC: 7111 AN: 1461340 Hom.: 27 Cov.: 33 AF XY: 0.00498 AC XY: 3623 AN XY: 727032

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00556

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00317 AC XY: 236 AN XY: 74426

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00538 Hom.: 4

Bravo AF: 0.00316

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00533

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

APEX1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	10
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs17112002; hg19: chr14-20925669;