X-123859895-C-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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.-431C>T		upstream_gene_variant		ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.-431C>T		upstream_gene_variant		1	NM_001167.4	ENSP00000360242.3

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

Gnomad4 AFR exome AF: 0.0183 AC: 72 AN: 3925

Gnomad4 AMR exome AF: 0.0350 AC: 309 AN: 8840

Gnomad4 ASJ exome AF: 0.0508 AC: 166 AN: 3265

Gnomad4 EAS exome AF: 0.000178 AC: 1 AN: 5614

Gnomad4 SAS exome AF: 0.0470 AC: 1163 AN: 24730

Gnomad4 FIN exome AF: 0.110 AC: 674 AN: 6149

Gnomad4 NFE exome AF: 0.0989 AC: 7910 AN: 79976

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0137 AC: 0.0137068 AN: 0.0137068

Gnomad4 AMR AF: 0.0458 AC: 0.045771 AN: 0.045771

Gnomad4 ASJ AF: 0.0560 AC: 0.0560394 AN: 0.0560394

Gnomad4 EAS AF: 0.000576 AC: 0.000576369 AN: 0.000576369

Gnomad4 SAS AF: 0.0316 AC: 0.0315543 AN: 0.0315543

Gnomad4 FIN AF: 0.0971 AC: 0.0970742 AN: 0.0970742

Gnomad4 NFE AF: 0.0917 AC: 0.0917482 AN: 0.0917482

Gnomad4 OTH AF: 0.0540 AC: 0.053964 AN: 0.053964

Alfa AF: 0.0834 Hom.: 3011

Bravo AF: 0.0549

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.15
DANN	Benign	0.92
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

Publications

LitVar

Other links and lift over

dbSNP: rs28382701; hg19: chrX-122993745;