Genetic Variant NM_001167.4:c.*80G>C (chrX-123907261-G-C) – ACMG Classification: Benign (-20 pts)

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.*80G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 915,101 control chromosomes in the GnomAD database, including 2,669 homozygotes. There are 21,564 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 ( 213 hom., 1974 hem., cov: 23)

Exomes 𝑓: 0.088 ( 2456 hom. 19590 hem. )

Consequence

XIAP
NM_001167.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0530

Publications

2 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: Labcorp Genetics (formerly Invitae), Orphanet

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=-0.82).

BP6

Variant X-123907261-G-C is Benign according to our data. Variant chrX-123907261-G-C is described in ClinVar as Benign. ClinVar VariationId is 367797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XIAP	NM_001167.4	MANE Select	c.*80G>C	3_prime_UTR	Exon 7 of 7	NP_001158.2
XIAP	NM_001204401.2		c.*80G>C	3_prime_UTR	Exon 7 of 7	NP_001191330.1	P98170
XIAP	NM_001378590.1		c.*80G>C	3_prime_UTR	Exon 7 of 7	NP_001365519.1	P98170

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XIAP	ENST00000371199.8	TSL:1 MANE Select	c.*80G>C	3_prime_UTR	Exon 7 of 7	ENSP00000360242.3	P98170
XIAP	ENST00000355640.3	TSL:5	c.*80G>C	3_prime_UTR	Exon 7 of 7	ENSP00000347858.3	P98170
XIAP	ENST00000422098.6	TSL:4	c.*80G>C	3_prime_UTR	Exon 9 of 9	ENSP00000405529.2	P98170

Frequencies

GnomAD3 genomes

AF:

0.0605

AC:

6748

AN:

111529

Hom.:

213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00878

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.0557

Gnomad EAS

AF:

0.000559

Gnomad SAS

AF:

0.0335

Gnomad FIN

AF:

0.0981

Gnomad MID

AF:

0.0336

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0514

GnomAD2 exomes

AF:

0.0637

AC:

8444

AN:

132506

AF XY:

0.0645

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0295

Gnomad ASJ exome

AF:

0.0504

Gnomad EAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.0941

Gnomad OTH exome

AF:

0.0597

GnomAD4 exome

AF:

0.0883

AC:

70937

AN:

803518

Hom.:

2456

Cov.:

AF XY:

0.0922

AC XY:

19590

AN XY:

212424

show subpopulations

African (AFR)

AF:

0.0139

AC:

282

AN:

20340

American (AMR)

AF:

0.0299

AC:

891

AN:

29823

Ashkenazi Jewish (ASJ)

AF:

0.0515

AC:

888

AN:

17240

East Asian (EAS)

AF:

0.000584

AC:

AN:

27382

South Asian (SAS)

AF:

0.0499

AC:

2257

AN:

45220

European-Finnish (FIN)

AF:

0.109

AC:

4208

AN:

38464

Middle Eastern (MID)

AF:

0.0640

AC:

208

AN:

3250

European-Non Finnish (NFE)

AF:

0.101

AC:

59392

AN:

585583

Other (OTH)

AF:

0.0772

AC:

2795

AN:

36216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2417

4833

7250

9666

12083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1934

3868

5802

7736

9670

<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:

0.0605

AC:

6749

AN:

111583

Hom.:

213

Cov.:

AF XY:

0.0584

AC XY:

1974

AN XY:

33809

show subpopulations

African (AFR)

AF:

0.0138

AC:

424

AN:

30831

American (AMR)

AF:

0.0457

AC:

476

AN:

10418

Ashkenazi Jewish (ASJ)

AF:

0.0557

AC:

147

AN:

2638

East Asian (EAS)

AF:

0.000560

AC:

AN:

3570

South Asian (SAS)

AF:

0.0333

AC:

AN:

2736

European-Finnish (FIN)

AF:

0.0981

AC:

579

AN:

5904

Middle Eastern (MID)

AF:

0.0415

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0930

AC:

4937

AN:

53069

Other (OTH)

AF:

0.0514

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

219

438

656

875

1094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0417

Hom.:

301

Bravo

AF:

0.0551

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

X-linked lymphoproliferative disease due to XIAP deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.7

(source)

DANN

Benign

0.79

PhyloP100

0.053

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over