Genetic Variant XBP1:c.453+395A>G (chr22-28796682-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000344347.6(XBP1):c.453+395A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 173,466 control chromosomes in the GnomAD database, including 18,353 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.44 ( 16996 hom., cov: 32)

Exomes 𝑓: 0.33 ( 1357 hom. )

Consequence

XBP1
ENST00000344347.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0440

Publications

46 publications found

Variant links:

Genes affected

XBP1 (HGNC:12801): (X-box binding protein 1) This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5. [provided by RefSeq, Jul 2008]

XBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

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

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
XBP1	NM_001079539.2 link	c.453+395A>G	intron_variant	Intron 3 of 5	NP_001073007.1	P17861-2
XBP1	NM_001393999.1 link	c.303+395A>G	intron_variant	Intron 3 of 5	NP_001380928.1
XBP1	NM_005080.4 link	c.453+395A>G	intron_variant	Intron 3 of 4	NP_005071.2	P17861-1A0A024R1F0
XBP1	NM_001394000.1 link	c.303+395A>G	intron_variant	Intron 3 of 4	NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6 link	c.453+395A>G		intron_variant	Intron 3 of 5	5		ENSP00000343155.5		P17861-2

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66503

AN:

151744

Hom.:

16944

Cov.:

show subpopulations

Gnomad AFR

AF:

0.690

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.315

Gnomad ASJ

AF:

0.333

Gnomad EAS

AF:

0.678

Gnomad SAS

AF:

0.537

Gnomad FIN

AF:

0.373

Gnomad MID

AF:

0.365

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.402

GnomAD4 exome

AF:

0.326

AC:

7034

AN:

21600

Hom.:

1357

Cov.:

AF XY:

0.332

AC XY:

3697

AN XY:

11128

show subpopulations

African (AFR)

AF:

0.690

AC:

280

AN:

406

American (AMR)

AF:

0.317

AC:

447

AN:

1410

Ashkenazi Jewish (ASJ)

AF:

0.275

AC:

157

AN:

570

East Asian (EAS)

AF:

0.662

AC:

368

AN:

556

South Asian (SAS)

AF:

0.471

AC:

790

AN:

1678

European-Finnish (FIN)

AF:

0.370

AC:

346

AN:

934

Middle Eastern (MID)

AF:

0.325

AC:

AN:

European-Non Finnish (NFE)

AF:

0.285

AC:

4165

AN:

14612

Other (OTH)

AF:

0.336

AC:

455

AN:

1354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

219

438

656

875

1094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.439

AC:

66619

AN:

151866

Hom.:

16996

Cov.:

AF XY:

0.440

AC XY:

32646

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.691

AC:

28601

AN:

41406

American (AMR)

AF:

0.316

AC:

4820

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

1155

AN:

3472

East Asian (EAS)

AF:

0.678

AC:

3481

AN:

5136

South Asian (SAS)

AF:

0.536

AC:

2575

AN:

4804

European-Finnish (FIN)

AF:

0.373

AC:

3918

AN:

10518

Middle Eastern (MID)

AF:

0.363

AC:

106

AN:

292

European-Non Finnish (NFE)

AF:

0.308

AC:

20938

AN:

67946

Other (OTH)

AF:

0.406

AC:

856

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1679

3358

5038

6717

8396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<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:

0.350

Hom.:

30658

Bravo

AF:

0.442

Asia WGS

AF:

0.619

AC:

2151

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.3

(source)

DANN

Benign

0.78

PhyloP100

-0.044

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

Computational scores

Splicing

Publications

Other links and lift over