14-20455692-A-G

Variant names:

• chr14-20455692-A-G
• rs778607554
• NM_001641.4:c.47A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001641.4(APEX1):​c.47A>G​(p.Glu16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1440497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.47A>G	p.Glu16Gly	missense_variant	Exon 2 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.47A>G	p.Glu16Gly	missense_variant	Exon 2 of 5		NP_001231178.1
APEX1	NM_080648.3	c.47A>G	p.Glu16Gly	missense_variant	Exon 2 of 5		NP_542379.1
APEX1	NM_080649.3	c.47A>G	p.Glu16Gly	missense_variant	Exon 2 of 5		NP_542380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.47A>G	p.Glu16Gly	missense_variant	Exon 2 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;T;T;T;.;T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.61	.;.;T;T;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.8	L;L;.;.;L;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.053	T;T;D;T;T;T;T;T
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D;D
Polyphen		0.61	P;P;.;.;P;.;.;.
Vest4		0.18
MutPred		0.21		Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);Gain of catalytic residue at R18 (P = 0.0127);
MVP		0.86
MPC		0.23
ClinPred		0.55	D
GERP RS		3.5
Varity_R		0.10
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778607554; hg19: chr14-20923851;