rs769664549

Variant names:

• chrX-123885766-A-G
• rs769664549
• NM_001167.4:c.104A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/21 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
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22292012).

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.104A>G	p.Asn35Ser	missense	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.104A>G	p.Asn35Ser	missense	Exon 2 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.104A>G	p.Asn35Ser	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.104A>G	p.Asn35Ser	missense	Exon 2 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000497640.1	TSL:1	n.100-2853A>G		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.104A>G	p.Asn35Ser	missense	Exon 2 of 7	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183053 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.0000568 AC: 2 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54115

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842100

Other (OTH) AF: 0.00 AC: 0 AN: 46091

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000824 AC: 1

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	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
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.10	N
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.85	T
Polyphen		0.16	B
Vest4		0.097
MutPred		0.52		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
Mutation Taster		=97/3	polymorphism

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: rs769664549; hg19: chrX-123019616;