rs5956583

chrX-123900661-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: 2.70

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]

ACMG classification

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	UniProt
XIAP	NM_001167.4	c.1268A>C	p.Gln423Pro	missense_variant	6/7	ENST00000371199.8

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.380 AC: 41899 AN: 110400 Hom.: 6048 Cov.: 22 AF XY: 0.363 AC XY: 11869 AN XY: 32672

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

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.: 32 AF XY: 0.350 AC XY: 127308 AN XY: 363279

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.: 22 AF XY: 0.363 AC XY: 11887 AN XY: 32734

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	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 -
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	-	- -

not provided Benign:2 Other:1

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	This variant is associated with the following publications: (PMID: 29248579, 19877056) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.036	T;T;T
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	T;.;.
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs5956583; hg19: chrX-123034511; COSMIC: COSV63022231; COSMIC: COSV63022231;