Genetic Variant XIAP:c.*5241A>T (chrX-123912422-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_001167.4(XIAP):c.*5241A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.59 ( 13895 hom., 17356 hem., cov: 20)

Exomes 𝑓: 0.57 ( 21417 hom. 49127 hem. )

Failed GnomAD Quality Control

Consequence

XIAP
NM_001167.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.26

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 (BayesDel_noAF=-1.06).

BP6

Variant X-123912422-A-T is Benign according to our data. Variant chrX-123912422-A-T is described in ClinVar as [Benign]. Clinvar id is 367848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4 link	c.*5241A>T		3_prime_UTR_variant	Exon 7 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.*5241A>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3		P98170
XIAP	ENST00000355640.3 link	c.*5241A>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3		P98170

Frequencies

GnomAD3 genomes

AF:

0.591

AC:

63440

AN:

107376

Hom.:

13896

Cov.:

AF XY:

0.580

AC XY:

17326

AN XY:

29896

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.434

Gnomad AMR

AF:

0.583

Gnomad ASJ

AF:

0.533

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.558

Gnomad FIN

AF:

0.641

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.560

Gnomad OTH

AF:

0.583

GnomAD3 exomes

AF:

0.565

AC:

52434

AN:

92733

Hom.:

9394

AF XY:

0.565

AC XY:

19685

AN XY:

34839

show subpopulations

Gnomad AFR exome

AF:

0.674

Gnomad AMR exome

AF:

0.551

Gnomad ASJ exome

AF:

0.545

Gnomad EAS exome

AF:

0.468

Gnomad SAS exome

AF:

0.592

Gnomad FIN exome

AF:

0.648

Gnomad NFE exome

AF:

0.563

Gnomad OTH exome

AF:

0.563

GnomAD4 exome

AF:

0.571

AC:

123226

AN:

215728

Hom.:

21417

Cov.:

AF XY:

0.572

AC XY:

49127

AN XY:

85938

show subpopulations

Gnomad4 AFR exome

AF:

0.678

Gnomad4 AMR exome

AF:

0.549

Gnomad4 ASJ exome

AF:

0.545

Gnomad4 EAS exome

AF:

0.455

Gnomad4 SAS exome

AF:

0.593

Gnomad4 FIN exome

AF:

0.653

Gnomad4 NFE exome

AF:

0.564

Gnomad4 OTH exome

AF:

0.575

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.591

AC:

63466

AN:

107408

Hom.:

13895

Cov.:

AF XY:

0.580

AC XY:

17356

AN XY:

29940

show subpopulations

Gnomad4 AFR

AF:

0.670

Gnomad4 AMR

AF:

0.583

Gnomad4 ASJ

AF:

0.533

Gnomad4 EAS

AF:

0.421

Gnomad4 SAS

AF:

0.560

Gnomad4 FIN

AF:

0.641

Gnomad4 NFE

AF:

0.560

Gnomad4 OTH

AF:

0.585

Alfa

AF:

0.568

Hom.:

6068

Bravo

AF:

0.596

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

X-linked lymphoproliferative disease due to XIAP deficiency

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.1

DANN

Benign

0.071

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