chrX-55002275-A-C

Variant names:

• chrX-55002275-A-C
• rs747835151
• NM_014481.4:c.266A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014481.4(APEX2):​c.266A>C​(p.Asn89Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,555 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N89S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054132402).

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.266A>C	p.Asn89Thr	missense	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-92+646A>C		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.266A>C	p.Asn89Thr	missense	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.266A>C	p.Asn89Thr	missense	Exon 3 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.266A>C	p.Asn89Thr	missense	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090555 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 357537

African (AFR) AF: 0.00 AC: 0 AN: 26225

American (AMR) AF: 0.00 AC: 0 AN: 34130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18803

East Asian (EAS) AF: 0.00 AC: 0 AN: 30116

South Asian (SAS) AF: 0.00 AC: 0 AN: 52210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838958

Other (OTH) AF: 0.00 AC: 0 AN: 45765

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.84
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.68	N
PhyloP100		0.34
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.10
Sift	Benign	0.29	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.068
MutPred		0.52		Loss of sheet (P = 0.0104)
MVP		0.33
MPC		0.15
ClinPred		0.20	T
GERP RS		4.4
Varity_R		0.079
gMVP		0.48
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747835151; hg19: chrX-55028708;