rs5956583

Positions:

chrX-123900661-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001167.4(XIAP):c.1268A>C(p.Gln423Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,208,247 control chromosomes in the GnomAD database, including 55,380 homozygotes. There are 139,195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 6055 hom., 11887 hem., cov: 22)

Exomes 𝑓: 0.36 ( 49325 hom. 127308 hem. )

Consequence

XIAP
NM_001167.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 2.70

Variant links:

Genes affected

XIAP (HGNC:592): (X-linked inhibitor of apoptosis) This gene encodes a protein that belongs to a family of apoptotic suppressor proteins. Members of this family share a conserved motif termed, baculovirus IAP repeat, which is necessary for their anti-apoptotic function. This protein functions through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme. This protein also inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. Mutations in this gene are the cause of X-linked lymphoproliferative syndrome. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.[provided by RefSeq, Feb 2011]

XIAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002920568).

BP6

Variant X-123900661-A-C is Benign according to our data. Variant chrX-123900661-A-C is described in ClinVar as [Benign]. Clinvar id is 257589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-123900661-A-C is described in Lovd as [Benign]. Variant chrX-123900661-A-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XIAP	NM_001167.4 linkuse as main transcript	c.1268A>C	p.Gln423Pro	missense_variant	6/7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8 linkuse as main transcript	c.1268A>C	p.Gln423Pro	missense_variant	6/7	1	NM_001167.4	ENSP00000360242	P1

Frequencies

GnomAD3 genomes

AF:

0.380

AC:

41899

AN:

110400

Hom.:

6048

Cov.:

AF XY:

0.363

AC XY:

11869

AN XY:

32672

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.351

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.0834

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.389

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.368

Gnomad OTH

AF:

0.372

GnomAD3 exomes

AF:

0.333

AC:

60908

AN:

183136

Hom.:

7197

AF XY:

0.323

AC XY:

21843

AN XY:

67646

show subpopulations

Gnomad AFR exome

AF:

0.469

Gnomad AMR exome

AF:

0.338

Gnomad ASJ exome

AF:

0.343

Gnomad EAS exome

AF:

0.0934

Gnomad SAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.365

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.357

AC:

391786

AN:

1097795

Hom.:

49325

Cov.:

AF XY:

0.350

AC XY:

127308

AN XY:

363279

show subpopulations

Gnomad4 AFR exome

AF:

0.474

Gnomad4 AMR exome

AF:

0.337

Gnomad4 ASJ exome

AF:

0.340

Gnomad4 EAS exome

AF:

0.0708

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.409

Gnomad4 NFE exome

AF:

0.373

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.380

AC:

41921

AN:

110452

Hom.:

6055

Cov.:

AF XY:

0.363

AC XY:

11887

AN XY:

32734

show subpopulations

Gnomad4 AFR

AF:

0.468

Gnomad4 AMR

AF:

0.351

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.0834

Gnomad4 SAS

AF:

0.168

Gnomad4 FIN

AF:

0.389

Gnomad4 NFE

AF:

0.368

Gnomad4 OTH

AF:

0.368

Alfa

AF:

0.361

Hom.:

17997

Bravo

AF:

0.387

TwinsUK

AF:

0.376

AC:

1396

ALSPAC

AF:

0.360

AC:

1039

ESP6500AA

AF:

0.472

AC:

1810

ESP6500EA

AF:

0.354

AC:

2379

ExAC

AF:

0.330

AC:

40047

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency

Benign:6

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 33. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	This variant is associated with the following publications: (PMID: 29248579, 19877056) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Autoinflammatory syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.036

T;T;T

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.47

T;.;.

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

M;M;M

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.098

MPC

0.27

ClinPred

0.013

GERP RS

4.6

Varity_R

0.31

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over