rs34632023

Variant names:

• chr14-20455971-G-A
• rs34632023
• NM_001641.4:c.116G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001641.4(APEX1):​c.116G>A​(p.Gly39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• Publications: 6 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31138664).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_001231178.1
APEX1	NM_080648.3	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_542379.1
APEX1	NM_080649.3	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.116G>A	p.Gly39Glu	missense_variant	Exon 3 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;T;T;T;T;T;.;T;T;T;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	.;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.1	L;L;.;.;L;.;.;.;.;.;.
PhyloP100		3.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.89	N;N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.097
Sift	Benign	0.078	T;T;D;D;T;D;T;D;D;D;D
Sift4G	Benign	0.45	T;T;T;T;T;T;T;D;T;T;T
Polyphen		0.0040	B;B;.;.;B;.;.;.;.;.;.
Vest4		0.36
MutPred		0.17		Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);Loss of ubiquitination at K35 (P = 0.0353);.;Loss of ubiquitination at K35 (P = 0.0353);.;.;
MVP		0.88
MPC		0.28
ClinPred		0.75	D
GERP RS		5.2
PromoterAI		-0.0011	Neutral
Varity_R		0.13
gMVP		0.48
Mutation Taster		=88/12	polymorphism

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: rs34632023; hg19: chr14-20924130;