NM_001641.4:c.134A>C

Variant names:

• chr14-20455989-A-C
• rs745852498
• NM_001641.4:c.134A>C

Variant summary

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

The NM_001641.4(APEX1):​c.134A>C​(p.Tyr45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: APEX1 NM_001641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX1	NM_001641.4	c.134A>C	p.Tyr45Ser	missense_variant	Exon 3 of 5	ENST00000216714.8	NP_001632.2
APEX1	NM_001244249.2	c.134A>C	p.Tyr45Ser	missense_variant	Exon 3 of 5		NP_001231178.1
APEX1	NM_080648.3	c.134A>C	p.Tyr45Ser	missense_variant	Exon 3 of 5		NP_542379.1
APEX1	NM_080649.3	c.134A>C	p.Tyr45Ser	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.134A>C	p.Tyr45Ser	missense_variant	Exon 3 of 5	1	NM_001641.4	ENSP00000216714.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 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: 0.0000387

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134A>C (p.Y45S) alteration is located in exon 3 (coding exon 2) of the APEX1 gene. This alteration results from a A to C substitution at nucleotide position 134, causing the tyrosine (Y) at amino acid position 45 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T;T;T;T;T;T;.;T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	.;.;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.7	L;L;.;.;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.050	N;N;N;N;N;N;N;D;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.21	T;T;T;D;T;T;T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99	D;D;.;.;D;.;.;.;.;.;.
Vest4		0.73
MutPred		0.30		Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);Gain of catalytic residue at P48 (P = 0.0016);.;Gain of catalytic residue at P48 (P = 0.0016);.;.;
MVP		0.89
MPC		0.86
ClinPred		0.88	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs745852498; hg19: chr14-20924148;