NM_014481.4:c.136C>T

Variant names:

• chrX-55000558-C-T
• rs935798554
• NM_014481.4:c.136C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_014481.4(APEX2):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,205,646 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520
• Publications: 0 publications found

Genes affected

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2896376).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX2	NM_014481.4	MANE Select	c.136C>T	p.Leu46Phe	missense	Exon 1 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-197C>T		5_prime_UTR	Exon 1 of 5	NP_001258677.1	B7ZA71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX2	ENST00000374987.4	TSL:1 MANE Select	c.136C>T	p.Leu46Phe	missense	Exon 1 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.136C>T	p.Leu46Phe	missense	Exon 1 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.136C>T	p.Leu46Phe	missense	Exon 1 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes AF: 0.0000802 AC: 9 AN: 112193 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000840

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

GnomAD2 exomes AF: 0.00000575 AC: 1 AN: 173768 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000235

GnomAD4 exome AF: 0.00000640 AC: 7 AN: 1093453 Hom.: 0 Cov.: 30 AF XY: 0.00000557 AC XY: 2 AN XY: 359127

African (AFR) AF: 0.00 AC: 0 AN: 26177

American (AMR) AF: 0.00 AC: 0 AN: 34314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19112

East Asian (EAS) AF: 0.00 AC: 0 AN: 29959

South Asian (SAS) AF: 0.00 AC: 0 AN: 53217

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40447

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4110

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840223

Other (OTH) AF: 0.000109 AC: 5 AN: 45894

GnomAD4 genome AF: 0.0000802 AC: 9 AN: 112193 Hom.: 0 Cov.: 23 AF XY: 0.000116 AC XY: 4 AN XY: 34343

African (AFR) AF: 0.00 AC: 0 AN: 30846

American (AMR) AF: 0.000840 AC: 9 AN: 10712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6129

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53150

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.00065	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.52
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.37
Sift	Benign	0.25	T
Sift4G	Benign	0.43	T
Polyphen		0.059	B
Vest4		0.27
MutPred		0.73		Gain of methylation at K50 (P = 0.0989)
MVP		0.86
MPC		0.19
ClinPred		0.13	T
GERP RS		1.6
PromoterAI		0.021	Neutral
Varity_R		0.12
gMVP		0.71
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs935798554; hg19: chrX-55026991;