NM_001167.4:c.*2845C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001167.4(XIAP):c.*2845C>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 326,921 control chromosomes in the GnomAD database, including 5,175 homozygotes. There are 28,723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 1513 hom., 6692 hem., cov: 23)

Exomes 𝑓: 0.24 ( 3662 hom. 22031 hem. )

Consequence

XIAP
NM_001167.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.234

Publications

9 publications found

Variant links:

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)

XIAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-123910026-C-T is Benign according to our data. Variant chrX-123910026-C-T is described in ClinVar as Benign. ClinVar VariationId is 367816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4 link	c.*2845C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000371199.8	NP_001158.2	P98170

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8 link	c.*2845C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3		P98170
XIAP	ENST00000355640.3 link	c.*2845C>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3		P98170

Frequencies

GnomAD3 genomes

AF:

0.196

AC:

21758

AN:

111056

Hom.:

1513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.189

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.387

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.315

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.197

GnomAD2 exomes

AF:

0.242

AC:

23854

AN:

98475

AF XY:

0.253

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.204

Gnomad EAS exome

AF:

0.373

Gnomad FIN exome

AF:

0.249

Gnomad NFE exome

AF:

0.196

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.237

AC:

51080

AN:

215811

Hom.:

3662

Cov.:

AF XY:

0.257

AC XY:

22031

AN XY:

85871

show subpopulations

African (AFR)

AF:

0.154

AC:

1052

AN:

6833

American (AMR)

AF:

0.211

AC:

4521

AN:

21416

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

1620

AN:

7973

East Asian (EAS)

AF:

0.363

AC:

2423

AN:

6678

South Asian (SAS)

AF:

0.387

AC:

13747

AN:

35541

European-Finnish (FIN)

AF:

0.244

AC:

2360

AN:

9660

Middle Eastern (MID)

AF:

0.287

AC:

236

AN:

822

European-Non Finnish (NFE)

AF:

0.195

AC:

22761

AN:

116461

Other (OTH)

AF:

0.226

AC:

2360

AN:

10427

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1463

2926

4388

5851

7314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.196

AC:

21764

AN:

111110

Hom.:

1513

Cov.:

AF XY:

0.201

AC XY:

6692

AN XY:

33336

show subpopulations

African (AFR)

AF:

0.149

AC:

4568

AN:

30681

American (AMR)

AF:

0.222

AC:

2305

AN:

10368

Ashkenazi Jewish (ASJ)

AF:

0.189

AC:

497

AN:

2634

East Asian (EAS)

AF:

0.333

AC:

1165

AN:

3500

South Asian (SAS)

AF:

0.387

AC:

1044

AN:

2699

European-Finnish (FIN)

AF:

0.258

AC:

1514

AN:

5867

Middle Eastern (MID)

AF:

0.315

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.192

AC:

10183

AN:

52965

Other (OTH)

AF:

0.203

AC:

307

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

637

1274

1912

2549

3186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.192

Hom.:

8303

Bravo

AF:

0.193

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.85

CADD

Benign

7.5

(source)

DANN

Benign

0.34

PhyloP100

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over