X-123911791-C-T

Variant names:

• chrX-123911791-C-T
• rs9856
• NM_001167.4:c.*4610C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*4610C>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 0.60 (13951 hom., 19708 hem., cov: 23)
  • Exomes 𝑓: 0.57 (21409 hom. 49131 hem.)
  • Failed GnomAD Quality Control
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.671
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-123911791-C-T is Benign according to our data. Variant chrX-123911791-C-T is described in ClinVar as Benign. ClinVar VariationId is 367837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*4610C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.*4610C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3
XIAP	ENST00000355640.3	c.*4610C>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.596 AC: 65961 AN: 110731 Hom.: 13951 Cov.: 23

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.560

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.590

GnomAD2 exomes AF: 0.566 AC: 52567 AN: 92905 AF XY: 0.566

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.571 AC: 123225 AN: 215734 Hom.: 21409 Cov.: 0 AF XY: 0.572 AC XY: 49131 AN XY: 85940

African (AFR) AF: 0.677 AC: 4624 AN: 6834

American (AMR) AF: 0.549 AC: 11776 AN: 21441

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 4348 AN: 7974

East Asian (EAS) AF: 0.455 AC: 3038 AN: 6684

South Asian (SAS) AF: 0.593 AC: 21139 AN: 35622

European-Finnish (FIN) AF: 0.653 AC: 6139 AN: 9398

Middle Eastern (MID) AF: 0.569 AC: 468 AN: 822

European-Non Finnish (NFE) AF: 0.564 AC: 65690 AN: 116528

Other (OTH) AF: 0.575 AC: 6003 AN: 10431

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.596 AC: 66006 AN: 110785 Hom.: 13951 Cov.: 23 AF XY: 0.596 AC XY: 19708 AN XY: 33047

African (AFR) AF: 0.674 AC: 20561 AN: 30526

American (AMR) AF: 0.588 AC: 6091 AN: 10366

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1407 AN: 2636

East Asian (EAS) AF: 0.427 AC: 1505 AN: 3521

South Asian (SAS) AF: 0.563 AC: 1499 AN: 2663

European-Finnish (FIN) AF: 0.663 AC: 3870 AN: 5838

Middle Eastern (MID) AF: 0.624 AC: 133 AN: 213

European-Non Finnish (NFE) AF: 0.563 AC: 29747 AN: 52828

Other (OTH) AF: 0.591 AC: 902 AN: 1526

Alfa AF: 0.574 Hom.: 67854

Bravo AF: 0.596

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.92
CADD	Benign	4.0
DANN	Benign	0.57
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9856; hg19: chrX-123045641;