rs138783302

Variant names:

• chrX-123886431-C-G
• rs138783302
• NM_001167.4:c.769C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001167.4(XIAP):​c.769C>G​(p.Pro257Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,209,593 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 571 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., 15 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (0 hom. 556 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.56
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03549859).
• BP6: Variant X-123886431-C-G is Benign according to our data. Variant chrX-123886431-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465073.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000722 (81/112159) while in subpopulation NFE AF = 0.00143 (76/53261). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 15 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	NM_001167.4	MANE Select	c.769C>G	p.Pro257Ala	missense	Exon 2 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.769C>G	p.Pro257Ala	missense	Exon 2 of 7	NP_001191330.1
	XIAP	NM_001378590.1		c.769C>G	p.Pro257Ala	missense	Exon 2 of 7	NP_001365519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.769C>G	p.Pro257Ala	missense	Exon 2 of 7	ENSP00000360242.3
	XIAP	ENST00000497640.1	TSL:1	n.100-2188C>G		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.769C>G	p.Pro257Ala	missense	Exon 2 of 7	ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 81 AN: 112104 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000663

GnomAD2 exomes AF: 0.000674 AC: 123 AN: 182389 AF XY: 0.000657

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000133

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.00152 AC: 1670 AN: 1097434 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 556 AN XY: 362942

African (AFR) AF: 0.000189 AC: 5 AN: 26402

American (AMR) AF: 0.0000852 AC: 3 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.000327 AC: 13 AN: 39751

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00191 AC: 1612 AN: 842112

Other (OTH) AF: 0.000803 AC: 37 AN: 46092

GnomAD4 genome AF: 0.000722 AC: 81 AN: 112159 Hom.: 0 Cov.: 23 AF XY: 0.000437 AC XY: 15 AN XY: 34325

African (AFR) AF: 0.0000647 AC: 2 AN: 30929

American (AMR) AF: 0.000192 AC: 2 AN: 10439

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3609

South Asian (SAS) AF: 0.00 AC: 0 AN: 2746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00143 AC: 76 AN: 53261

Other (OTH) AF: 0.000655 AC: 1 AN: 1527

Alfa AF: 0.00125 Hom.: 21

Bravo AF: 0.000880

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00277 AC: 8

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00208 AC: 14

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00158

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	X-linked lymphoproliferative disease due to XIAP deficiency (3)
-	-	2	not provided (2)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	XIAP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.091
Sift	Uncertain	0.021	D
Sift4G	Benign	0.29	T
Polyphen		0.56	P
Vest4		0.49
MVP		0.21
MPC		0.22
ClinPred		0.063	T
GERP RS		4.9
Varity_R		0.24
gMVP		0.71
Mutation Taster		=98/2	polymorphism (auto)

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: rs138783302; hg19: chrX-123020281;