X-123885802-T-C

Variant names:

• chrX-123885802-T-C
• NM_001167.4:c.140T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001167.4(XIAP):​c.140T>C​(p.Leu47Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	NM_001167.4	MANE Select	c.140T>C	p.Leu47Pro	missense	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.140T>C	p.Leu47Pro	missense	Exon 2 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.140T>C	p.Leu47Pro	missense	Exon 2 of 7	NP_001365519.1	P98170

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.140T>C	p.Leu47Pro	missense	Exon 2 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000497640.1	TSL:1	n.100-2817T>C		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.140T>C	p.Leu47Pro	missense	Exon 2 of 7	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked lymphoproliferative disease due to XIAP deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.92		Gain of disorder (P = 0.01)
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0
Mutation Taster		=11/89	disease causing

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

hg19: chrX-123019652;