22-28800481-G-A

Position:

chr22-28800481-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001079539.2(XBP1):c.44C>T(p.Pro15Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00383 in 1,486,008 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 10 hom. )

Consequence

XBP1
NM_001079539.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 4.58

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:

XBP1 (HGNC:):

XBP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008250654).

BP6

Variant 22-28800481-G-A is Benign according to our data. Variant chr22-28800481-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1255617.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XBP1	NM_001079539.2 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	1/6		NP_001073007.1	P17861-2
XBP1	NM_005080.4 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	1/5		NP_005071.2	P17861-1A0A024R1F0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
XBP1	ENST00000344347.6 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	1/6	5	ENSP00000343155.5	P17861-2
XBP1	ENST00000216037.10 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	1/5	1	ENSP00000216037.6	P17861-1
XBP1	ENST00000403532.7 linkuse as main transcript	c.44C>T	p.Pro15Leu	missense_variant	1/5	3	ENSP00000385162.3	B1AHH2
XBP1	ENST00000482720.1 linkuse as main transcript	n.89C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0145

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00256

AC:

213

AN:

83348

Hom.:

AF XY:

0.00248

AC XY:

121

AN XY:

48710

show subpopulations

Gnomad AFR exome

AF:

0.00131

Gnomad AMR exome

AF:

0.000997

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.00350

Gnomad OTH exome

AF:

0.00220

GnomAD4 exome

AF:

0.00392

AC:

5223

AN:

1333772

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

2472

AN XY:

658766

show subpopulations

Gnomad4 AFR exome

AF:

0.000793

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0111

Gnomad4 NFE exome

AF:

0.00432

Gnomad4 OTH exome

AF:

0.00322

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152236

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000723

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0145

Gnomad4 NFE

AF:

0.00388

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00239

Hom.:

Bravo

AF:

0.00194

ExAC

AF:

0.00110

AC:

109

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Autosomal dominant polycystic liver disease

Benign:1

Likely benign, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;T;T;.

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.4

M;.;M;M

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.0

D;D;.;D

REVEL

Benign

0.091

Sift

Benign

0.036

D;D;.;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.74

.;.;P;P

Vest4

0.27

MVP

0.42

MPC

0.96

ClinPred

0.076

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.33

gMVP

0.51

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over