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GeneBe

22-28797139-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001079539.2(XBP1):c.391C>G(p.Gln131Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

XBP1
NM_001079539.2 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13021928).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
XBP1NM_001079539.2 linkuse as main transcriptc.391C>G p.Gln131Glu missense_variant 3/6 ENST00000344347.6
XBP1NM_001393999.1 linkuse as main transcriptc.241C>G p.Gln81Glu missense_variant 3/6
XBP1NM_005080.4 linkuse as main transcriptc.391C>G p.Gln131Glu missense_variant 3/5
XBP1NM_001394000.1 linkuse as main transcriptc.241C>G p.Gln81Glu missense_variant 3/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XBP1ENST00000344347.6 linkuse as main transcriptc.391C>G p.Gln131Glu missense_variant 3/65 NM_001079539.2 P4P17861-2
XBP1ENST00000216037.10 linkuse as main transcriptc.391C>G p.Gln131Glu missense_variant 3/51 A2P17861-1
XBP1ENST00000403532.7 linkuse as main transcriptc.406C>G p.Gln136Glu missense_variant 3/53 A2
XBP1ENST00000405219.7 linkuse as main transcriptc.241C>G p.Gln81Glu missense_variant 3/52

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000559
AC:
14
AN:
250546
Hom.:
0
AF XY:
0.0000738
AC XY:
10
AN XY:
135484
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000398
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000411
AC:
60
AN:
1461134
Hom.:
0
Cov.:
30
AF XY:
0.0000385
AC XY:
28
AN XY:
726936
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000191
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000459
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 19, 2022The c.391C>G (p.Q131E) alteration is located in exon 3 (coding exon 3) of the XBP1 gene. This alteration results from a C to G substitution at nucleotide position 391, causing the glutamine (Q) at amino acid position 131 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.22
Cadd
Benign
20
Dann
Uncertain
0.98
DEOGEN2
Benign
0.11
T;T;.;T;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.91
D;D;D;D;.
M_CAP
Benign
0.0021
T
MetaRNN
Benign
0.13
T;T;T;T;T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
1.2
L;.;L;.;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.52
N;N;.;N;N
REVEL
Benign
0.12
Sift
Benign
0.75
T;T;.;T;T
Sift4G
Benign
0.84
T;T;T;T;T
Polyphen
0.068, 0.97
.;.;B;D;B
Vest4
0.25
MutPred
0.36
.;.;.;Gain of loop (P = 0.0851);.;
MVP
0.36
MPC
1.0
ClinPred
0.10
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.16
gMVP
0.45

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.

Other links and lift over

dbSNP: rs770180123; hg19: chr22-29193127; API