chrX-123859895-C-T

Position:

• chrX-123859895-C-T

Variant summary

Our verdict is Benign. Variant got -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 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
• 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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
XIAP	NM_001204401.2	c.-43C>T		5_prime_UTR_variant	1/7		NP_001191330.1
XIAP	NM_001378591.1	c.-170C>T		5_prime_UTR_variant	1/8		NP_001365520.1
XIAP	NM_001378592.1	c.-33+157C>T		intron_variant			NP_001365521.1
XIAP	NR_165803.1	n.86C>T		non_coding_transcript_exon_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000422098.6	c.-170C>T		5_prime_UTR_variant	2/9	4		ENSP00000405529	P1
XIAP	ENST00000430625.1	c.-43C>T		5_prime_UTR_variant	1/2	3		ENSP00000400637
XIAP	ENST00000468691.5	n.19C>T		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 6617 AN: 110313 Hom.: 207 Cov.: 24 AF XY: 0.0575 AC XY: 1879 AN XY: 32701

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

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0508

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0470

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0989

Gnomad4 OTH exome AF: 0.0823

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

Gnomad4 AMR AF: 0.0458

Gnomad4 ASJ AF: 0.0560

Gnomad4 EAS AF: 0.000576

Gnomad4 SAS AF: 0.0316

Gnomad4 FIN AF: 0.0971

Gnomad4 NFE AF: 0.0917

Gnomad4 OTH AF: 0.0540

Alfa AF: 0.0839 Hom.: 2626

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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;