22-28794483-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001079539.2(XBP1):​c.*692A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,420 control chromosomes in the GnomAD database, including 1,183 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 0.11 ( 1181 hom., cov: 32)
Exomes 𝑓: 0.17 ( 2 hom. )

Consequence

XBP1
NM_001079539.2 downstream_gene

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0510
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XBP1NM_001079539.2 linkc.*692A>G downstream_gene_variant NP_001073007.1 P17861-2
XBP1NM_001393999.1 linkc.*692A>G downstream_gene_variant NP_001380928.1
XBP1NM_005080.4 linkc.*1063A>G downstream_gene_variant NP_005071.2 P17861-1A0A024R1F0
XBP1NM_001394000.1 linkc.*1063A>G downstream_gene_variant NP_001380929.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XBP1ENST00000344347.6 linkc.*692A>G downstream_gene_variant 5 ENSP00000343155.5 P17861-2

Frequencies

GnomAD3 genomes
AF:
0.115
AC:
17487
AN:
152158
Hom.:
1183
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0660
Gnomad AMI
AF:
0.0910
Gnomad AMR
AF:
0.0851
Gnomad ASJ
AF:
0.130
Gnomad EAS
AF:
0.206
Gnomad SAS
AF:
0.281
Gnomad FIN
AF:
0.101
Gnomad MID
AF:
0.203
Gnomad NFE
AF:
0.133
Gnomad OTH
AF:
0.139
GnomAD4 exome
AF:
0.167
AC:
24
AN:
144
Hom.:
2
AF XY:
0.176
AC XY:
13
AN XY:
74
show subpopulations
Gnomad4 EAS exome
AF:
0.172
Gnomad4 NFE exome
AF:
0.125
GnomAD4 genome
AF:
0.115
AC:
17480
AN:
152276
Hom.:
1181
Cov.:
32
AF XY:
0.116
AC XY:
8603
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0658
Gnomad4 AMR
AF:
0.0850
Gnomad4 ASJ
AF:
0.130
Gnomad4 EAS
AF:
0.205
Gnomad4 SAS
AF:
0.280
Gnomad4 FIN
AF:
0.101
Gnomad4 NFE
AF:
0.133
Gnomad4 OTH
AF:
0.138
Alfa
AF:
0.119
Hom.:
467
Bravo
AF:
0.110
Asia WGS
AF:
0.239
AC:
834
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
1.5
DANN
Benign
0.42

Splicing

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: rs2267131; hg19: chr22-29190471; API