chrX-55006857-C-T

Position:

• chrX-55006857-C-T

Variant summary

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

The NM_014481.4(APEX2):​c.979C>T​(p.Arg327Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,210,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 127 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (0 hom. 116 hem.)
• Consequence: APEX2 NM_014481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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=0.024210751).
• BS2: High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APEX2	NM_014481.4	c.979C>T	p.Arg327Cys	missense_variant	6/6	ENST00000374987.4
APEX2	NM_001271748.2	c.466C>T	p.Arg156Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APEX2	ENST00000374987.4	c.979C>T	p.Arg327Cys	missense_variant	6/6	1	NM_014481.4	P1

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 32 AN: 112071 Hom.: 0 Cov.: 23 AF XY: 0.000321 AC XY: 11 AN XY: 34249

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000350 AC: 64 AN: 182782 Hom.: 0 AF XY: 0.000342 AC XY: 23 AN XY: 67264

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00181

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000376

Gnomad NFE exome AF: 0.000307

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000340 AC: 373 AN: 1098056 Hom.: 0 Cov.: 31 AF XY: 0.000319 AC XY: 116 AN XY: 363414

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000861

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.000247

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.000325

GnomAD4 genome AF: 0.000285 AC: 32 AN: 112128 Hom.: 0 Cov.: 23 AF XY: 0.000321 AC XY: 11 AN XY: 34316

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00113

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000561

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000327

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000456 Hom.: 16

Bravo AF: 0.000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000491

EpiControl AF: 0.000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.979C>T (p.R327C) alteration is located in exon 6 (coding exon 6) of the APEX2 gene. This alteration results from a C to T substitution at nucleotide position 979, causing the arginine (R) at amino acid position 327 to be replaced by a cysteine (C). 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	0.076
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.12
Sift	Benign	0.055	T
Sift4G	Uncertain	0.030	D
Polyphen		0.30	B
Vest4		0.17
MVP		0.33
MPC		0.23
ClinPred		0.077	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.76

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: rs138407648; hg19: chrX-55033290;