X-55006683-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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 id is 2660688.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX2	NM_014481.4	c.805C>T	p.His269Tyr	missense_variant	Exon 6 of 6	ENST00000374987.4	NP_055296.2
APEX2	NM_001271748.2	c.292C>T	p.His98Tyr	missense_variant	Exon 5 of 5		NP_001258677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX2	ENST00000374987.4	c.805C>T	p.His269Tyr	missense_variant	Exon 6 of 6	1	NM_014481.4	ENSP00000364126.3
APEX2	ENST00000471758.1	n.654C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes AF: 0.000258 AC: 29 AN: 112245 Hom.: 0 Cov.: 23 AF XY: 0.000291 AC XY: 10 AN XY: 34389

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

GnomAD3 exomes AF: 0.000490 AC: 68 AN: 138647 Hom.: 0 AF XY: 0.000614 AC XY: 23 AN XY: 37453

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 SAS exome AF: 0.00501

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

Gnomad4 AFR exome AF: 0.0000397

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00555

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000363

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

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00131

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APEX2: BS2 -

Computational scores

Source: dbNSFP v4.3

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs145122391; hg19: chrX-55033116; COSMIC: COSV58189869; COSMIC: COSV58189869;