NM_014481.4:c.373C>T

Variant names:

• chrX-55002382-C-T
• rs764508954
• NM_014481.4:c.373C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014481.4(APEX2):​c.373C>T​(p.Arg125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000853 in 1,208,141 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000089 (0 hom. 29 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 4 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 29 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.373C>T	p.Arg125Trp	missense	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-91-580C>T		intron	N/A	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.373C>T	p.Arg125Trp	missense	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.373C>T	p.Arg125Trp	missense	Exon 3 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.373C>T	p.Arg125Trp	missense	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes AF: 0.0000532 AC: 6 AN: 112881 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000112

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000394 AC: 7 AN: 177748 AF XY: 0.0000480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000886 AC: 97 AN: 1095260 Hom.: 0 Cov.: 31 AF XY: 0.0000804 AC XY: 29 AN XY: 360862

African (AFR) AF: 0.00 AC: 0 AN: 26317

American (AMR) AF: 0.0000575 AC: 2 AN: 34767

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19164

East Asian (EAS) AF: 0.00 AC: 0 AN: 30156

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53413

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40435

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.000108 AC: 91 AN: 840923

Other (OTH) AF: 0.0000653 AC: 3 AN: 45964

GnomAD4 genome AF: 0.0000532 AC: 6 AN: 112881 Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1 AN XY: 35027

African (AFR) AF: 0.00 AC: 0 AN: 31073

American (AMR) AF: 0.00 AC: 0 AN: 10777

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.00 AC: 0 AN: 2739

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000112 AC: 6 AN: 53341

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

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	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.72
MPC		0.64
ClinPred		0.81	D
GERP RS		3.8
Varity_R		0.40
gMVP		0.64
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs764508954; hg19: chrX-55028815;