X-123885766-A-G

Variant summary

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

The NM_001167.4(XIAP):c.104A>G(p.Asn35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,134 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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=0.22292012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIAP	NM_001167.4	c.104A>G	p.Asn35Ser	missense_variant	2/7	ENST00000371199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIAP	ENST00000371199.8	c.104A>G	p.Asn35Ser	missense_variant	2/7	1	NM_001167.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183053 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67675

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098134 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

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

Invitae

Mar 22, 2023

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. 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. This variant has not been reported in the literature in individuals affected with XIAP-related conditions. This variant is present in population databases (rs769664549, gnomAD 0.008%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 35 of the XIAP protein (p.Asn35Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.050	T;.;T;T
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.66	T;T;.;.
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.10	N;.;N;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.31	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.16	B;.;B;B
Vest4		0.097
MutPred		0.52		Loss of catalytic residue at N35 (P = 0.0408);Loss of catalytic residue at N35 (P = 0.0408);Loss of catalytic residue at N35 (P = 0.0408);Loss of catalytic residue at N35 (P = 0.0408);
MVP		0.39
MPC		0.21
ClinPred		0.070	T
GERP RS		5.8
Varity_R		0.19
gMVP		0.49

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: rs769664549; hg19: chrX-123019616;