14-20457047-G-C

Variant names:

• chr14-20457047-G-C
• rs780293860
• NM_001641.4:c.496G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001641.4(APEX1):​c.496G>C​(p.Val166Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34101903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.496G>C	p.Val166Leu	missense_variant	Exon 5 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.496G>C	p.Val166Leu	missense_variant	Exon 5 of 5		NP_001231178.1
APEX1	NM_080648.3	c.496G>C	p.Val166Leu	missense_variant	Exon 5 of 5		NP_542379.1
APEX1	NM_080649.3	c.496G>C	p.Val166Leu	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.496G>C	p.Val166Leu	missense_variant	Exon 5 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251260 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T;T;T;T;T;T;.
Eigen	Benign	-0.072
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	.;.;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.80	N;N;.;N;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.14	N;N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.016	D;D;D;D;T;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;T;T;T
Polyphen		0.13	B;B;.;B;.;.;.
Vest4		0.37
MutPred		0.65		Gain of catalytic residue at D163 (P = 0.0018);Gain of catalytic residue at D163 (P = 0.0018);Gain of catalytic residue at D163 (P = 0.0018);Gain of catalytic residue at D163 (P = 0.0018);Gain of catalytic residue at D163 (P = 0.0018);.;.;
MVP		0.84
MPC		0.28
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.34
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs780293860; hg19: chr14-20925206;