X-123912065-C-T

Variant names:

• chrX-123912065-C-T
• rs8371
• NM_001167.4:c.*4884C>T

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.*4884C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 325,624 control chromosomes in the GnomAD database, including 5,174 homozygotes. There are 28,453 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1512 hom., 6360 hem., cov: 21)
  • Exomes 𝑓: 0.24 (3662 hom. 22093 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.793
• Publications: 8 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=-0.88).
• BP6: Variant X-123912065-C-T is Benign according to our data. Variant chrX-123912065-C-T is described in ClinVar as Benign. ClinVar VariationId is 367838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*4884C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.*4884C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3
XIAP	ENST00000355640.3	c.*4884C>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 21409 AN: 109835 Hom.: 1512 Cov.: 21

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.245 AC: 23237 AN: 94756 AF XY: 0.258

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.374

Gnomad FIN exome AF: 0.250

Gnomad NFE exome AF: 0.197

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.237 AC: 51119 AN: 215751 Hom.: 3662 Cov.: 0 AF XY: 0.257 AC XY: 22093 AN XY: 85953

African (AFR) AF: 0.154 AC: 1052 AN: 6832

American (AMR) AF: 0.211 AC: 4532 AN: 21437

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 1623 AN: 7975

East Asian (EAS) AF: 0.363 AC: 2428 AN: 6684

South Asian (SAS) AF: 0.387 AC: 13792 AN: 35631

European-Finnish (FIN) AF: 0.245 AC: 2305 AN: 9399

Middle Eastern (MID) AF: 0.287 AC: 236 AN: 823

European-Non Finnish (NFE) AF: 0.196 AC: 22789 AN: 116541

Other (OTH) AF: 0.226 AC: 2362 AN: 10429

GnomAD4 genome AF: 0.195 AC: 21409 AN: 109873 Hom.: 1512 Cov.: 21 AF XY: 0.198 AC XY: 6360 AN XY: 32157

African (AFR) AF: 0.148 AC: 4475 AN: 30258

American (AMR) AF: 0.222 AC: 2260 AN: 10196

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 502 AN: 2634

East Asian (EAS) AF: 0.335 AC: 1164 AN: 3472

South Asian (SAS) AF: 0.385 AC: 988 AN: 2568

European-Finnish (FIN) AF: 0.251 AC: 1408 AN: 5600

Middle Eastern (MID) AF: 0.314 AC: 65 AN: 207

European-Non Finnish (NFE) AF: 0.192 AC: 10117 AN: 52758

Other (OTH) AF: 0.210 AC: 315 AN: 1503

Alfa AF: 0.191 Hom.: 4271

Bravo AF: 0.193

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

X-linked lymphoproliferative disease due to XIAP deficiency Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		0.79
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: rs8371; hg19: chrX-123045915;