X-123885786-G-A

Position:

• chrX-123885786-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001167.4(XIAP):​c.124G>A​(p.Val42Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19861269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XIAP	NM_001167.4	c.124G>A	p.Val42Ile	missense_variant	2/7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.124G>A	p.Val42Ile	missense_variant	2/7	1	NM_001167.4	ENSP00000360242	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098216 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000237

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 42 of the XIAP protein (p.Val42Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with XIAP-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XIAP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.071	T;.;T;T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.70	T;T;.;.
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.3	L;.;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.049	D;T;D;D
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.46	P;.;P;P
Vest4		0.090
MutPred		0.46		Loss of glycosylation at S38 (P = 0.1228);Loss of glycosylation at S38 (P = 0.1228);Loss of glycosylation at S38 (P = 0.1228);Loss of glycosylation at S38 (P = 0.1228);
MVP		0.34
MPC		0.38
ClinPred		0.50	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1236823622; hg19: chrX-123019636;