chrX-123885786-G-A

Variant names:

• chrX-123885786-G-A
• rs1236823622
• NM_001167.4:c.124G>A

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.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. 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: 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
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

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=0.19861269).

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.124G>A	p.Val42Ile	missense	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.124G>A	p.Val42Ile	missense	Exon 2 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.124G>A	p.Val42Ile	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.124G>A	p.Val42Ile	missense	Exon 2 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000497640.1	TSL:1	n.100-2833G>A		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.124G>A	p.Val42Ile	missense	Exon 2 of 7	ENSP00000347858.3	P98170

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

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 842121

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.083
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.071	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.069
Sift	Benign	0.049	D
Sift4G	Benign	0.14	T
Polyphen		0.46	P
Vest4		0.090
MutPred		0.46		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
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1236823622; hg19: chrX-123019636;