14-20456995-T-G

Variant names:

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

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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 421 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 (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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX1	NM_001641.4	MANE Select	c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	NP_001632.2
	APEX1	NM_001244249.2		c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	NP_001231178.1	Q5TZP7
	APEX1	NM_080648.3		c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	NP_542379.1	Q5TZP7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX1	ENST00000216714.8	TSL:1 MANE Select	c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	ENSP00000216714.3	P27695
	APEX1	ENST00000398030.8	TSL:1	c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	ENSP00000381111.4	P27695
	APEX1	ENST00000555414.5	TSL:1	c.444T>G	p.Asp148Glu	missense	Exon 5 of 5	ENSP00000451979.1	P27695

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

GnomAD2 exomes AF: 0.421 AC: 104602 AN: 248646 AF XY: 0.415

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 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

African (AFR) AF: 0.358 AC: 11985 AN: 33474

American (AMR) AF: 0.386 AC: 17199 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 9315 AN: 26114

East Asian (EAS) AF: 0.396 AC: 15709 AN: 39670

South Asian (SAS) AF: 0.241 AC: 20788 AN: 86172

European-Finnish (FIN) AF: 0.515 AC: 27431 AN: 53310

Middle Eastern (MID) AF: 0.367 AC: 2117 AN: 5768

European-Non Finnish (NFE) AF: 0.480 AC: 533786 AN: 1111218

Other (OTH) AF: 0.434 AC: 26169 AN: 60344

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

African (AFR) AF: 0.357 AC: 14801 AN: 41482

American (AMR) AF: 0.413 AC: 6305 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1247 AN: 3470

East Asian (EAS) AF: 0.393 AC: 2035 AN: 5176

South Asian (SAS) AF: 0.240 AC: 1159 AN: 4822

European-Finnish (FIN) AF: 0.524 AC: 5547 AN: 10586

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32603 AN: 67974

Other (OTH) AF: 0.436 AC: 920 AN: 2110

Alfa AF: 0.456 Hom.: 63101

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	APEX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.12
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.29		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
Mutation Taster		=99/1	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: rs1130409; hg19: chr14-20925154; COSMIC: COSV51657755; COSMIC: COSV51657755;