NM_001204401.2:c.-43C>T

Variant names:

• chrX-123859895-C-T
• rs28382701
• NM_001204401.2:c.-43C>T

Variant summary

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

The NM_001204401.2(XIAP):​c.-43C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.07 in 250,379 control chromosomes in the GnomAD database, including 539 homozygotes. There are 5,545 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (207 hom., 1879 hem., cov: 24)
  • Exomes 𝑓: 0.078 (332 hom. 3666 hem.)
• Consequence: XIAP NM_001204401.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-123859895-C-T is Benign according to our data. Variant chrX-123859895-C-T is described in ClinVar as Benign. ClinVar VariationId is 1278675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204401.2. 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_001204401.2		c.-43C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001191330.1	P98170
	XIAP	NM_001378591.1		c.-170C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001365520.1	P98170
	XIAP	NM_001204401.2		c.-43C>T		5_prime_UTR	Exon 1 of 7	NP_001191330.1	P98170

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000422098.6	TSL:4	c.-170C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000405529.2	P98170
	XIAP	ENST00000430625.1	TSL:3	c.-43C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000400637.1	B1AKU2
	XIAP	ENST00000422098.6	TSL:4	c.-170C>T		5_prime_UTR	Exon 2 of 9	ENSP00000405529.2	P98170

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 6617 AN: 110313 Hom.: 207 Cov.: 24

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00746

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0560

Gnomad EAS AF: 0.000574

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0971

Gnomad MID AF: 0.0383

Gnomad NFE AF: 0.0917

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0779 AC: 10902 AN: 140020 Hom.: 332 Cov.: 0 AF XY: 0.0744 AC XY: 3666 AN XY: 49284

African (AFR) AF: 0.0183 AC: 72 AN: 3925

American (AMR) AF: 0.0350 AC: 309 AN: 8840

Ashkenazi Jewish (ASJ) AF: 0.0508 AC: 166 AN: 3265

East Asian (EAS) AF: 0.000178 AC: 1 AN: 5614

South Asian (SAS) AF: 0.0470 AC: 1163 AN: 24730

European-Finnish (FIN) AF: 0.110 AC: 674 AN: 6149

Middle Eastern (MID) AF: 0.0563 AC: 26 AN: 462

European-Non Finnish (NFE) AF: 0.0989 AC: 7910 AN: 79976

Other (OTH) AF: 0.0823 AC: 581 AN: 7059

GnomAD4 genome AF: 0.0600 AC: 6618 AN: 110359 Hom.: 207 Cov.: 24 AF XY: 0.0574 AC XY: 1879 AN XY: 32757

African (AFR) AF: 0.0137 AC: 416 AN: 30350

American (AMR) AF: 0.0458 AC: 480 AN: 10487

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 148 AN: 2641

East Asian (EAS) AF: 0.000576 AC: 2 AN: 3470

South Asian (SAS) AF: 0.0316 AC: 81 AN: 2567

European-Finnish (FIN) AF: 0.0971 AC: 574 AN: 5913

Middle Eastern (MID) AF: 0.0467 AC: 10 AN: 214

European-Non Finnish (NFE) AF: 0.0917 AC: 4821 AN: 52546

Other (OTH) AF: 0.0540 AC: 81 AN: 1501

Alfa AF: 0.0834 Hom.: 3011

Bravo AF: 0.0549

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.15
DANN	Benign	0.92
PhyloP100		-1.2
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs28382701; hg19: chrX-122993745;