14-20457251-C-G

Variant names:

• chr14-20457251-C-G
• NM_001641.4:c.700C>G

Variant summary

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

The NM_001641.4(APEX1):​c.700C>G​(p.Pro234Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81

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=0.30454516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.700C>G	p.Pro234Ala	missense_variant	Exon 5 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.700C>G	p.Pro234Ala	missense_variant	Exon 5 of 5		NP_001231178.1
APEX1	NM_080648.3	c.700C>G	p.Pro234Ala	missense_variant	Exon 5 of 5		NP_542379.1
APEX1	NM_080649.3	c.700C>G	p.Pro234Ala	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.700C>G	p.Pro234Ala	missense_variant	Exon 5 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.42	T;T;T;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.95	.;.;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.1	M;M;.;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.29	T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		0.054	B;B;.;B;.
Vest4		0.21
MutPred		0.55		Gain of catalytic residue at A230 (P = 0.0026);Gain of catalytic residue at A230 (P = 0.0026);Gain of catalytic residue at A230 (P = 0.0026);Gain of catalytic residue at A230 (P = 0.0026);.;
MVP		0.90
MPC		0.17
ClinPred		0.19	T
GERP RS		5.8
Varity_R		0.48
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-20925410;