dbSNP rs35873774: XBP1:c.573+103T>C (chr22-28795944-A-G) – 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.573+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,504,106 control chromosomes in the GnomAD database, including 2,629 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 0.045 ( 204 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2425 hom. )

Consequence

XBP1
ENST00000344347.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

20 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:

Genome browser will be placed here

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=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
XBP1	NM_001079539.2 link	c.573+103T>C	intron_variant	Intron 5 of 5	NP_001073007.1	P17861-2
XBP1	NM_001393999.1 link	c.423+103T>C	intron_variant	Intron 5 of 5	NP_001380928.1
XBP1	NM_005080.4 link	c.599+103T>C	intron_variant	Intron 4 of 4	NP_005071.2	P17861-1A0A024R1F0
XBP1	NM_001394000.1 link	c.449+103T>C	intron_variant	Intron 4 of 4	NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6 link	c.573+103T>C		intron_variant	Intron 5 of 5	5		ENSP00000343155.5		P17861-2

Frequencies

GnomAD3 genomes

AF:

0.0450

AC:

6848

AN:

152172

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0205

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0304

Gnomad FIN

AF:

0.0851

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0652

Gnomad OTH

AF:

0.0282

GnomAD4 exome

AF:

0.0560

AC:

75662

AN:

1351816

Hom.:

2425

AF XY:

0.0552

AC XY:

37329

AN XY:

676270

show subpopulations

African (AFR)

AF:

0.0189

AC:

592

AN:

31348

American (AMR)

AF:

0.0187

AC:

791

AN:

42370

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

304

AN:

24092

East Asian (EAS)

AF:

0.000153

AC:

AN:

39166

South Asian (SAS)

AF:

0.0258

AC:

2073

AN:

80470

European-Finnish (FIN)

AF:

0.0822

AC:

3990

AN:

48566

Middle Eastern (MID)

AF:

0.0173

AC:

AN:

5032

European-Non Finnish (NFE)

AF:

0.0636

AC:

65181

AN:

1024094

Other (OTH)

AF:

0.0465

AC:

2638

AN:

56678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3488

6975

10463

13950

17438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2306

4612

6918

9224

11530

<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:

0.0450

AC:

6847

AN:

152290

Hom.:

204

Cov.:

AF XY:

0.0450

AC XY:

3354

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0204

AC:

846

AN:

41572

American (AMR)

AF:

0.0256

AC:

391

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0310

AC:

150

AN:

4832

European-Finnish (FIN)

AF:

0.0851

AC:

903

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0652

AC:

4431

AN:

68008

Other (OTH)

AF:

0.0279

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

342

684

1025

1367

1709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0508

Hom.:

Bravo

AF:

0.0383

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

8.9

(source)

DANN

Benign

0.65

PhyloP100

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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