rs749097921

Variant names:

• chr14-20457452-C-A
• NM_001641.4:c.901C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-20457452-C-A
• chr14-20457452-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001641.4(APEX1):​c.901C>A​(p.Arg301Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.34

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]

PIP4P1 (HGNC:19299): (phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1) TMEM55B catalyzes the degradation of phosphatidylinositol 4,5-bisphosphate (PtdIns-4,5-P2) by removing the 4-phosphate (Ungewickell et al., 2005 [PubMed 16365287]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a mutagenesis_site Reduces the interaction with TOMM20. Abolishes localization in the mitochondria; when associated with A-299. (size 0) in uniprot entity APEX1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.901C>A	p.Arg301Ser	missense_variant	Exon 5 of 5	ENST00000216714.8	NP_001632.2
PIP4P1	NM_144568.4	c.*1107G>T		downstream_gene_variant		ENST00000250489.9	NP_653169.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX1	ENST00000216714.8	c.901C>A	p.Arg301Ser	missense_variant	Exon 5 of 5	1	NM_001641.4	ENSP00000216714.3
PIP4P1	ENST00000250489.9	c.*1107G>T		downstream_gene_variant		1	NM_144568.4	ENSP00000250489.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.37	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.58		Gain of catalytic residue at K299 (P = 0.001);Gain of catalytic residue at K299 (P = 0.001);Gain of catalytic residue at K299 (P = 0.001);
MVP		0.86
MPC		0.76
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.82

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: chr14-20925611;