ENST00000344347.6:c.19G>A

Variant summary

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

The ENST00000344347.6(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
ENST00000344347.6 missense

Scores

1
3
14

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]

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XBP1NM_001079539.2 linkc.19G>A p.Ala7Thr missense_variant Exon 1 of 6 NP_001073007.1 P17861-2
XBP1NM_005080.4 linkc.19G>A p.Ala7Thr missense_variant Exon 1 of 5 NP_005071.2 P17861-1A0A024R1F0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
XBP1ENST00000344347.6 linkc.19G>A p.Ala7Thr missense_variant Exon 1 of 6 5 ENSP00000343155.5 P17861-2

Frequencies

GnomAD3 genomes
AF:
0.103
AC:
15623
AN:
152086
Hom.:
1098
Cov.:
33
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.:
32
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
0
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
0
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.:
33
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:
62
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
0
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
0
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 v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
T;T;.;.
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.71
T;T;T;.
MetaRNN
Benign
0.0020
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
M;.;M;M
PhyloP100
0.83
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.49
N;N;.;N
REVEL
Benign
0.054
Sift
Benign
0.033
D;D;.;D
Sift4G
Benign
0.32
T;T;T;T
Polyphen
0.017
.;.;B;B
Vest4
0.30
MPC
0.85
ClinPred
0.047
T
GERP RS
3.4
PromoterAI
0.027
Neutral
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)

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: rs5762809; hg19: chr22-29196494; COSMIC: COSV53274088; COSMIC: COSV53274088; API