NM_014481.4:c.805C>T

Variant names:

• chrX-55006683-C-T
• rs145122391
• NM_014481.4:c.805C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014481.4(APEX2):​c.805C>T​(p.His269Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,165,491 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00041 (0 hom. 185 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00992167).
• BP6: Variant X-55006683-C-T is Benign according to our data. Variant chrX-55006683-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2660688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 10 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.805C>T	p.His269Tyr	missense	Exon 6 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.292C>T	p.His98Tyr	missense	Exon 5 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.805C>T	p.His269Tyr	missense	Exon 6 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.760C>T	p.His254Tyr	missense	Exon 6 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.658C>T	p.His220Tyr	missense	Exon 5 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 29 AN: 112245 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000490 AC: 68 AN: 138647 AF XY: 0.000614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000223

Gnomad OTH exome AF: 0.000895

GnomAD4 exome AF: 0.000406 AC: 428 AN: 1053190 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 185 AN XY: 335570

African (AFR) AF: 0.0000397 AC: 1 AN: 25202

American (AMR) AF: 0.00 AC: 0 AN: 29820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16545

East Asian (EAS) AF: 0.00 AC: 0 AN: 29566

South Asian (SAS) AF: 0.00555 AC: 260 AN: 46870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38941

Middle Eastern (MID) AF: 0.00483 AC: 19 AN: 3930

European-Non Finnish (NFE) AF: 0.000161 AC: 132 AN: 818252

Other (OTH) AF: 0.000363 AC: 16 AN: 44064

GnomAD4 genome AF: 0.000258 AC: 29 AN: 112301 Hom.: 0 Cov.: 23 AF XY: 0.000290 AC XY: 10 AN XY: 34455

African (AFR) AF: 0.0000323 AC: 1 AN: 30953

American (AMR) AF: 0.00 AC: 0 AN: 10689

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.00560 AC: 15 AN: 2680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6159

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000207 AC: 11 AN: 53193

Other (OTH) AF: 0.00131 AC: 2 AN: 1529

Alfa AF: 0.000255 Hom.: 1

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000803 AC: 97

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.12
Sift	Benign	0.091	T
Sift4G	Uncertain	0.020	D
Polyphen		0.75	P
Vest4		0.035
MVP		0.49
MPC		0.17
ClinPred		0.042	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.37
Mutation Taster		=93/7	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: rs145122391; hg19: chrX-55033116; COSMIC: COSV58189869; COSMIC: COSV58189869;