rs33956927

chr14-20457272-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001641.4(APEX1):c.721G>A(p.Gly241Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,614,210 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (9 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.93

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=0.008568823).
• BP6: Variant 14-20457272-G-A is Benign according to our data. Variant chr14-20457272-G-A is described in ClinVar as [Benign]. Clinvar id is 709908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00519 (791/152320) while in subpopulation AFR AF= 0.0183 (761/41574). AF 95% confidence interval is 0.0172. There are 11 homozygotes in gnomad4. There are 377 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APEX1	NM_001641.4	c.721G>A	p.Gly241Arg	missense_variant	5/5	ENST00000216714.8
APEX1	NM_001244249.2	c.721G>A	p.Gly241Arg	missense_variant	5/5
APEX1	NM_080648.3	c.721G>A	p.Gly241Arg	missense_variant	5/5
APEX1	NM_080649.3	c.721G>A	p.Gly241Arg	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APEX1	ENST00000216714.8	c.721G>A	p.Gly241Arg	missense_variant	5/5	1	NM_001641.4	P1

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 792 AN: 152202 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00138 AC: 348 AN: 251496 Hom.: 3 AF XY: 0.00100 AC XY: 136 AN XY: 135922

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000575 AC: 840 AN: 1461890 Hom.: 9 Cov.: 33 AF XY: 0.000498 AC XY: 362 AN XY: 727246

Gnomad4 AFR exome AF: 0.0199

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00519 AC: 791 AN: 152320 Hom.: 11 Cov.: 33 AF XY: 0.00506 AC XY: 377 AN XY: 74478

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000754 Hom.: 1

Bravo AF: 0.00565

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00166 AC: 201

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

APEX1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2019

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	0.26
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	0.50	N;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.41	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.030	D;D;D;D;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.45
MutPred		0.51		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);.;
MVP		0.82
MPC		0.74
ClinPred		0.030	T
GERP RS		5.6
Varity_R		0.83
gMVP		0.85

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: rs33956927; hg19: chr14-20925431;