NM_001079539.2:c.19G>A

Variant names:

Variant summary

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

The NM_001079539.2(XBP1):c.19G>A(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,488,060 control chromosomes in the GnomAD database, including 14,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1096 hom., cov: 33)

Exomes 𝑓: 0.14 ( 13721 hom. )

Consequence

XBP1
NM_001079539.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.826

Publications

22 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001998186).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.19G>A	p.Ala7Thr	missense	Exon 1 of 6	NP_001073007.1
	XBP1	NM_005080.4		c.19G>A	p.Ala7Thr	missense	Exon 1 of 5	NP_005071.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
XBP1	ENST00000344347.6	TSL:5 MANE Select	c.19G>A	p.Ala7Thr	missense	Exon 1 of 6	ENSP00000343155.5
XBP1	ENST00000216037.10	TSL:1	c.19G>A	p.Ala7Thr	missense	Exon 1 of 5	ENSP00000216037.6
XBP1	ENST00000403532.7	TSL:3	c.19G>A	p.Ala7Thr	missense	Exon 1 of 5	ENSP00000385162.3

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15623

AN:

152086

Hom.:

1098

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0244

Gnomad AMI

AF:

0.0872

Gnomad AMR

AF:

0.0814

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.206

Gnomad SAS

AF:

0.281

Gnomad FIN

AF:

0.100

Gnomad MID

AF:

0.204

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.131

GnomAD2 exomes

AF:

0.146

AC:

12511

AN:

85718

AF XY:

0.157

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.0596

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.136

AC:

182292

AN:

1335866

Hom.:

13721

Cov.:

AF XY:

0.140

AC XY:

92656

AN XY:

659754

show subpopulations

African (AFR)

AF:

0.0231

AC:

614

AN:

26614

American (AMR)

AF:

0.0672

AC:

1793

AN:

26688

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

2969

AN:

22894

East Asian (EAS)

AF:

0.206

AC:

6204

AN:

30074

South Asian (SAS)

AF:

0.265

AC:

19478

AN:

73512

European-Finnish (FIN)

AF:

0.108

AC:

3743

AN:

34746

Middle Eastern (MID)

AF:

0.216

AC:

1143

AN:

5292

European-Non Finnish (NFE)

AF:

0.131

AC:

138605

AN:

1060608

Other (OTH)

AF:

0.140

AC:

7743

AN:

55438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

8364

16728

25092

33456

41820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5180

10360

15540

20720

25900

<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:

0.103

AC:

15614

AN:

152194

Hom.:

1096

Cov.:

AF XY:

0.104

AC XY:

7725

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0243

AC:

1011

AN:

41534

American (AMR)

AF:

0.0813

AC:

1244

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

452

AN:

3472

East Asian (EAS)

AF:

0.206

AC:

1062

AN:

5166

South Asian (SAS)

AF:

0.280

AC:

1353

AN:

4824

European-Finnish (FIN)

AF:

0.100

AC:

1063

AN:

10612

Middle Eastern (MID)

AF:

0.212

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.133

AC:

9013

AN:

67986

Other (OTH)

AF:

0.130

AC:

275

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

752

1504

2257

3009

3761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<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:

0.125

Hom.:

759

Bravo

AF:

0.0958

TwinsUK

AF:

0.146

AC:

543

ALSPAC

AF:

0.130

AC:

501

ExAC

AF:

0.0871

AC:

8079

Asia WGS

AF:

0.238

AC:

827

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

PhyloP100

0.83

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.49

REVEL

Benign

0.054

Sift

Benign

0.033

Sift4G

Benign

0.32

Polyphen

0.017

Vest4

0.30

MPC

0.85

ClinPred

0.047

GERP RS

3.4

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.078

gMVP

0.41

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over