dbSNP rs34842534: XBP1:c.573+137C>T (chr22-28795910-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001079539.2(XBP1):c.573+137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,286,768 control chromosomes in the GnomAD database, including 53 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 0.0054 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0071 ( 50 hom. )

Consequence

XBP1
NM_001079539.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.139

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00706 (8009/1134534) while in subpopulation MID AF= 0.0186 (70/3770). AF 95% confidence interval is 0.0151. There are 50 homozygotes in gnomad4_exome. There are 4105 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
XBP1	NM_001079539.2 link	c.573+137C>T	intron_variant	Intron 5 of 5	NP_001073007.1	P17861-2
XBP1	NM_001393999.1 link	c.423+137C>T	intron_variant	Intron 5 of 5	NP_001380928.1
XBP1	NM_005080.4 link	c.599+137C>T	intron_variant	Intron 4 of 4	NP_005071.2	P17861-1A0A024R1F0
XBP1	NM_001394000.1 link	c.449+137C>T	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+137C>T		intron_variant	Intron 5 of 5	5		ENSP00000343155.5		P17861-2

Frequencies

GnomAD3 genomes

AF:

0.00540

AC:

822

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00865

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00715

Gnomad OTH

AF:

0.00765

GnomAD4 exome

AF:

0.00706

AC:

8009

AN:

1134534

Hom.:

AF XY:

0.00718

AC XY:

4105

AN XY:

571832

show subpopulations

Gnomad4 AFR exome

AF:

0.000893

Gnomad4 AMR exome

AF:

0.00638

Gnomad4 ASJ exome

AF:

0.0231

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.000516

Gnomad4 NFE exome

AF:

0.00713

Gnomad4 OTH exome

AF:

0.00833

GnomAD4 genome

AF:

0.00541

AC:

824

AN:

152234

Hom.:

Cov.:

AF XY:

0.00559

AC XY:

416

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.00863

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0104

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00716

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00526

Hom.:

Bravo

AF:

0.00598

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.94

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over