22-28800428-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001079539.2(XBP1):c.97G>A(p.Gly33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,488,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

XBP1
NM_001079539.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.898

Publications

0 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:

ENSG00000226471 (HGNC:):

ENSG00000226471 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007114202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079539.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.97G>A	p.Gly33Ser	missense	Exon 1 of 6	NP_001073007.1	P17861-2
	XBP1	NM_005080.4		c.97G>A	p.Gly33Ser	missense	Exon 1 of 5	NP_005071.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XBP1	ENST00000344347.6	TSL:5 MANE Select	c.97G>A	p.Gly33Ser	missense	Exon 1 of 6	ENSP00000343155.5	P17861-2
XBP1	ENST00000216037.10	TSL:1	c.97G>A	p.Gly33Ser	missense	Exon 1 of 5	ENSP00000216037.6	P17861-1
XBP1	ENST00000933819.1		c.97G>A	p.Gly33Ser	missense	Exon 1 of 4	ENSP00000603878.1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000298

AC:

AN:

80522

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.000548

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000166

Gnomad OTH exome

AF:

0.000459

GnomAD4 exome

AF:

0.0000823

AC:

110

AN:

1336066

Hom.:

Cov.:

AF XY:

0.0000804

AC XY:

AN XY:

659148

show subpopulations

African (AFR)

AF:

0.0000375

AC:

AN:

26652

American (AMR)

AF:

0.000963

AC:

AN:

24918

Ashkenazi Jewish (ASJ)

AF:

0.000572

AC:

AN:

22720

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.0000137

AC:

AN:

72954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.000612

AC:

AN:

4904

European-Non Finnish (NFE)

AF:

0.0000510

AC:

AN:

1057944

Other (OTH)

AF:

0.000253

AC:

AN:

55242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000269

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41580

American (AMR)

AF:

0.00170

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000172

Hom.:

Bravo

AF:

0.000325

ExAC

AF:

0.0000990

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.59

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0071

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.90

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.13

REVEL

Benign

0.14

Sift

Benign

0.50

Sift4G

Benign

0.27

Polyphen

0.80

Vest4

0.16

MutPred

0.047

Gain of glycosylation at G33 (P = 0.0136)

MVP

0.27

MPC

0.30

ClinPred

0.083

GERP RS

2.9

PromoterAI

-0.0082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.10

gMVP

0.41

Mutation Taster

=72/28

polymorphism

(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