rs35873774

Variant summary

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

The ENST00000344347.6(XBP1):​c.573+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,504,106 control chromosomes in the GnomAD database, including 2,629 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 0.045 ( 204 hom., cov: 32)
Exomes 𝑓: 0.056 ( 2425 hom. )

Consequence

XBP1
ENST00000344347.6 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

20 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]

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 (BayesDel_noAF=-0.84).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XBP1NM_001079539.2 linkc.573+103T>C intron_variant Intron 5 of 5 NP_001073007.1 P17861-2
XBP1NM_001393999.1 linkc.423+103T>C intron_variant Intron 5 of 5 NP_001380928.1
XBP1NM_005080.4 linkc.599+103T>C intron_variant Intron 4 of 4 NP_005071.2 P17861-1A0A024R1F0
XBP1NM_001394000.1 linkc.449+103T>C intron_variant Intron 4 of 4 NP_001380929.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XBP1ENST00000344347.6 linkc.573+103T>C intron_variant Intron 5 of 5 5 ENSP00000343155.5 P17861-2

Frequencies

GnomAD3 genomes
AF:
0.0450
AC:
6848
AN:
152172
Hom.:
204
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0205
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.0256
Gnomad ASJ
AF:
0.0182
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0304
Gnomad FIN
AF:
0.0851
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0652
Gnomad OTH
AF:
0.0282
GnomAD4 exome
AF:
0.0560
AC:
75662
AN:
1351816
Hom.:
2425
AF XY:
0.0552
AC XY:
37329
AN XY:
676270
show subpopulations
African (AFR)
AF:
0.0189
AC:
592
AN:
31348
American (AMR)
AF:
0.0187
AC:
791
AN:
42370
Ashkenazi Jewish (ASJ)
AF:
0.0126
AC:
304
AN:
24092
East Asian (EAS)
AF:
0.000153
AC:
6
AN:
39166
South Asian (SAS)
AF:
0.0258
AC:
2073
AN:
80470
European-Finnish (FIN)
AF:
0.0822
AC:
3990
AN:
48566
Middle Eastern (MID)
AF:
0.0173
AC:
87
AN:
5032
European-Non Finnish (NFE)
AF:
0.0636
AC:
65181
AN:
1024094
Other (OTH)
AF:
0.0465
AC:
2638
AN:
56678
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
3488
6975
10463
13950
17438
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2306
4612
6918
9224
11530
<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:
0.0450
AC:
6847
AN:
152290
Hom.:
204
Cov.:
32
AF XY:
0.0450
AC XY:
3354
AN XY:
74466
show subpopulations
African (AFR)
AF:
0.0204
AC:
846
AN:
41572
American (AMR)
AF:
0.0256
AC:
391
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.0182
AC:
63
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.0310
AC:
150
AN:
4832
European-Finnish (FIN)
AF:
0.0851
AC:
903
AN:
10610
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.0652
AC:
4431
AN:
68008
Other (OTH)
AF:
0.0279
AC:
59
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
342
684
1025
1367
1709
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
88
176
264
352
440
<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:
0.0508
Hom.:
71
Bravo
AF:
0.0383
Asia WGS
AF:
0.0110
AC:
38
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
8.9
DANN
Benign
0.65
PhyloP100
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs35873774; hg19: chr22-29191932; API