chrX-55002385-G-T

Variant names:

• chrX-55002385-G-T
• rs762024105
• NM_014481.4:c.376G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014481.4(APEX2):​c.376G>T​(p.Ala126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,094,366 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000030 (0 hom. 13 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.689

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03372696).
• BS2: High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX2	NM_014481.4	c.376G>T	p.Ala126Ser	missense_variant	Exon 3 of 6	ENST00000374987.4	NP_055296.2
APEX2	NM_001271748.2	c.-91-577G>T		intron_variant	Intron 2 of 4		NP_001258677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX2	ENST00000374987.4	c.376G>T	p.Ala126Ser	missense_variant	Exon 3 of 6	1	NM_014481.4	ENSP00000364126.3
APEX2	ENST00000471758.1	n.272-577G>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000340 AC: 6 AN: 176502 Hom.: 0 AF XY: 0.0000326 AC XY: 2 AN XY: 61292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000444

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 33 AN: 1094366 Hom.: 0 Cov.: 31 AF XY: 0.0000361 AC XY: 13 AN XY: 360022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00109

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000227

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>T (p.A126S) alteration is located in exon 3 (coding exon 3) of the APEX2 gene. This alteration results from a G to T substitution at nucleotide position 376, causing the alanine (A) at amino acid position 126 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.067
Sift	Benign	0.58	T
Sift4G	Benign	0.79	T
Polyphen		0.030	B
Vest4		0.050
MutPred		0.38		Loss of sheet (P = 0.0228);
MVP		0.64
MPC		0.14
ClinPred		0.080	T
GERP RS		4.8
Varity_R		0.082
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762024105; hg19: chrX-55028818;