rs1301444460

Variant names:

• chrX-55001614-C-T
• rs1301444460
• NM_014481.4:c.226C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001271748.2(APEX2):​c.-107C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000275 in 1,090,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: APEX2 NM_001271748.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271748.2. 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.226C>T	p.Arg76Cys	missense	Exon 2 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-107C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	NP_001258677.1	B7ZA71
	APEX2	NM_001271748.2		c.-107C>T		5_prime_UTR	Exon 2 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.226C>T	p.Arg76Cys	missense	Exon 2 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.226C>T	p.Arg76Cys	missense	Exon 2 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.226C>T	p.Arg76Cys	missense	Exon 2 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1090158 Hom.: 0 Cov.: 29 AF XY: 0.00000561 AC XY: 2 AN XY: 356196

African (AFR) AF: 0.00 AC: 0 AN: 26235

American (AMR) AF: 0.00 AC: 0 AN: 34479

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19200

East Asian (EAS) AF: 0.00 AC: 0 AN: 29990

South Asian (SAS) AF: 0.00 AC: 0 AN: 52394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 837762

Other (OTH) AF: 0.00 AC: 0 AN: 45804

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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	0.11
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.78		Loss of disorder (P = 0.0138)
MVP		0.70
MPC		0.75
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.82
Mutation Taster		=35/65	disease causing

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: rs1301444460; hg19: chrX-55028047; COSMIC: COSV100895151; COSMIC: COSV100895151;