rs5956583

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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

Publications

44 publications found

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 Gene-Disease associations (from GenCC):

X-linked lymphoproliferative disease due to XIAP deficiency
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

XIAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 257589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
XIAP	NM_001167.4 link	c.1268A>C	p.Gln423Pro	missense_variant	Exon 6 of 7	ENST00000371199.8	NP_001158.2	P98170

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8 link	c.1268A>C	p.Gln423Pro	missense_variant	Exon 6 of 7	1	NM_001167.4	ENSP00000360242.3		P98170

Frequencies

GnomAD3 genomes

AF:

0.380

AC:

41899

AN:

110400

Hom.:

6048

Cov.:

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

GnomAD2 exomes

AF:

0.333

AC:

60908

AN:

183136

AF XY:

0.323

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 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

African (AFR)

AF:

0.474

AC:

12512

AN:

26392

American (AMR)

AF:

0.337

AC:

11855

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

6598

AN:

19381

East Asian (EAS)

AF:

0.0708

AC:

2137

AN:

30198

South Asian (SAS)

AF:

0.200

AC:

10854

AN:

54140

European-Finnish (FIN)

AF:

0.409

AC:

16559

AN:

40512

Middle Eastern (MID)

AF:

0.296

AC:

1222

AN:

4127

European-Non Finnish (NFE)

AF:

0.373

AC:

313883

AN:

841771

Other (OTH)

AF:

0.351

AC:

16166

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

9287

18574

27862

37149

46436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10636

21272

31908

42544

53180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.380

AC:

41921

AN:

110452

Hom.:

6055

Cov.:

AF XY:

0.363

AC XY:

11887

AN XY:

32734

show subpopulations

African (AFR)

AF:

0.468

AC:

14208

AN:

30339

American (AMR)

AF:

0.351

AC:

3614

AN:

10293

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

902

AN:

2635

East Asian (EAS)

AF:

0.0834

AC:

294

AN:

3526

South Asian (SAS)

AF:

0.168

AC:

450

AN:

2674

European-Finnish (FIN)

AF:

0.389

AC:

2247

AN:

5769

Middle Eastern (MID)

AF:

0.285

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.368

AC:

19423

AN:

52832

Other (OTH)

AF:

0.368

AC:

552

AN:

1502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

919

1837

2756

3674

4593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.372

Hom.:

21300

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Apr 05, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3Other:1

Aug 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29248579, 19877056) -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

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. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autoinflammatory syndrome

Benign:1

Jan 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.7

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over