chrX-123911259-C-A

Variant names:

• chrX-123911259-C-A
• rs28382751
• NM_001167.4:c.*4078C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*4078C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 106,268 control chromosomes in the GnomAD database, including 1,301 homozygotes. There are 5,727 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (1301 hom., 5727 hem., cov: 21)
  • Exomes 𝑓: 0.23 (3580 hom. 21461 hem.)
  • Failed GnomAD Quality Control
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.202
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-123911259-C-A is Benign according to our data. Variant chrX-123911259-C-A is described in ClinVar as Benign. ClinVar VariationId is 367831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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.*4078C>A		3_prime_UTR	Exon 7 of 7	NP_001158.2
	XIAP	NR_037916.2		n.4936C>A		non_coding_transcript_exon	Exon 6 of 6
	XIAP	NR_165803.1		n.4918C>A		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.*4078C>A		3_prime_UTR	Exon 7 of 7	ENSP00000360242.3
	XIAP	ENST00000355640.3	TSL:5	c.*4078C>A		3_prime_UTR	Exon 7 of 7	ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 18907 AN: 106214 Hom.: 1300 Cov.: 21

Gnomad AFR AF: 0.0792

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.191

GnomAD2 exomes AF: 0.238 AC: 21825 AN: 91765 AF XY: 0.249

Gnomad AFR exome AF: 0.0653

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.372

Gnomad FIN exome AF: 0.245

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.229

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.235 AC: 49868 AN: 212360 Hom.: 3580 Cov.: 0 AF XY: 0.256 AC XY: 21461 AN XY: 83704

African (AFR) AF: 0.0820 AC: 488 AN: 5953

American (AMR) AF: 0.208 AC: 4392 AN: 21166

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 1603 AN: 7870

East Asian (EAS) AF: 0.363 AC: 2419 AN: 6657

South Asian (SAS) AF: 0.388 AC: 13714 AN: 35367

European-Finnish (FIN) AF: 0.245 AC: 2295 AN: 9349

Middle Eastern (MID) AF: 0.282 AC: 227 AN: 804

European-Non Finnish (NFE) AF: 0.195 AC: 22447 AN: 114918

Other (OTH) AF: 0.222 AC: 2283 AN: 10276

GnomAD4 genome AF: 0.178 AC: 18911 AN: 106268 Hom.: 1301 Cov.: 21 AF XY: 0.181 AC XY: 5727 AN XY: 31560

African (AFR) AF: 0.0792 AC: 2134 AN: 26931

American (AMR) AF: 0.214 AC: 2182 AN: 10173

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 497 AN: 2631

East Asian (EAS) AF: 0.337 AC: 1160 AN: 3439

South Asian (SAS) AF: 0.382 AC: 985 AN: 2577

European-Finnish (FIN) AF: 0.248 AC: 1410 AN: 5689

Middle Eastern (MID) AF: 0.298 AC: 64 AN: 215

European-Non Finnish (NFE) AF: 0.192 AC: 10085 AN: 52499

Other (OTH) AF: 0.197 AC: 285 AN: 1444

Alfa AF: 0.0663 Hom.: 259

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs28382751; hg19: chrX-123045109;