chr14-20456995-T-G

Variant names:

• chr14-20456995-T-G
• rs1130409
• NM_001641.4:c.444T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001641.4(APEX1):​c.444T>G​(p.Asp148Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,612,734 control chromosomes in the GnomAD database, including 169,093 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14357 hom., cov: 33)
  • Exomes 𝑓: 0.45 (154736 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.117

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4034252E-4).
• BP6: Variant 14-20456995-T-G is Benign according to our data. Variant chr14-20456995-T-G is described in ClinVar as [Benign]. Clinvar id is 1297236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.444T>G	p.Asp148Glu	missense_variant	Exon 5 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.444T>G	p.Asp148Glu	missense_variant	Exon 5 of 5		NP_001231178.1
APEX1	NM_080648.3	c.444T>G	p.Asp148Glu	missense_variant	Exon 5 of 5		NP_542379.1
APEX1	NM_080649.3	c.444T>G	p.Asp148Glu	missense_variant	Exon 5 of 5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.444T>G	p.Asp148Glu	missense_variant	Exon 5 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes AF: 0.428 AC: 65059 AN: 151990 Hom.: 14342 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.421 AC: 104602 AN: 248646 Hom.: 22885 AF XY: 0.415 AC XY: 55788 AN XY: 134488

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.399

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.480

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.455 AC: 664499 AN: 1460626 Hom.: 154736 Cov.: 55 AF XY: 0.449 AC XY: 325960 AN XY: 726542

Gnomad4 AFR exome AF: 0.358

Gnomad4 AMR exome AF: 0.386

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.396

Gnomad4 SAS exome AF: 0.241

Gnomad4 FIN exome AF: 0.515

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.428 AC: 65134 AN: 152108 Hom.: 14357 Cov.: 33 AF XY: 0.428 AC XY: 31844 AN XY: 74364

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.413

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.393

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.436

Alfa AF: 0.459 Hom.: 32318

Bravo AF: 0.423

TwinsUK AF: 0.496 AC: 1838

ALSPAC AF: 0.470 AC: 1813

ESP6500AA AF: 0.366 AC: 1611

ESP6500EA AF: 0.471 AC: 4054

ExAC AF: 0.420 AC: 50974

Asia WGS AF: 0.305 AC: 1064 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24892639, 24076439, 23038158, 20530453, 21198260, 16621887, 17028303, 22466227, 23369758, 22184996, 22224629, 22193858, 18823566, 21538578, 19762350, 11024165, 19041121, 10371543, 23776569, 27050370, 24310503, 24523018, 26257461) -

APEX1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.4
DANN	Benign	0.66
DEOGEN2	Benign	0.16	T;T;T;T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	.;.;T;T;T;T;T
MetaRNN	Benign	0.00034	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N;.;N;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.20	N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.;.
Vest4		0.025
MutPred		0.29		Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);Gain of catalytic residue at D148 (P = 0.0041);.;.;
MPC		0.16
ClinPred		0.0026	T
GERP RS		-2.6
Varity_R		0.23
gMVP		0.36

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: rs1130409; hg19: chr14-20925154; COSMIC: COSV51657755; COSMIC: COSV51657755;