rs5762809

Positions:

• chr22-28800506-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001079539.2(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. 11/19 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 NM_001079539.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.19G>A	p.Ala7Thr	missense_variant	1/6		NP_001073007.1
XBP1	NM_005080.4	c.19G>A	p.Ala7Thr	missense_variant	1/5		NP_005071.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.19G>A	p.Ala7Thr	missense_variant	1/6	5		ENSP00000343155.5
XBP1	ENST00000216037.10	c.19G>A	p.Ala7Thr	missense_variant	1/5	1		ENSP00000216037.6
XBP1	ENST00000403532.7	c.19G>A	p.Ala7Thr	missense_variant	1/5	3		ENSP00000385162.3
XBP1	ENST00000482720.1	n.64G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15623 AN: 152086 Hom.: 1098 Cov.: 33

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

GnomAD3 exomes AF: 0.146 AC: 12511 AN: 85718 Hom.: 1185 AF XY: 0.157 AC XY: 7825 AN XY: 49830

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 SAS exome AF: 0.265

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

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.0672

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.103 AC: 15614 AN: 152194 Hom.: 1096 Cov.: 33 AF XY: 0.104 AC XY: 7725 AN XY: 74428

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.0813

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.206

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.130

Alfa AF: 0.126 Hom.: 539

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.078
gMVP		0.41

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

Other links and lift over

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