rs2228260

chr22-28800318-G-Achr22-28800318-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001079539.2(XBP1):c.207C>T(p.Pro69=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,555,012 control chromosomes in the GnomAD database, including 1,709 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 0.033 (169 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1540 hom.)
• Consequence: XBP1 NM_001079539.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.425

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XBP1	NM_001079539.2	c.207C>T	p.Pro69=	synonymous_variant	1/6	ENST00000344347.6
XBP1	NM_005080.4	c.207C>T	p.Pro69=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.207C>T	p.Pro69=	synonymous_variant	1/6	5	NM_001079539.2	P4
XBP1	ENST00000216037.10	c.207C>T	p.Pro69=	synonymous_variant	1/5	1		A2
XBP1	ENST00000403532.7	c.207C>T	p.Pro69=	synonymous_variant	1/5	3		A2
XBP1	ENST00000482720.1	n.252C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4999 AN: 152168 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0584 AC: 8813 AN: 150948 Hom.: 427 AF XY: 0.0578 AC XY: 4817 AN XY: 83308

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.100

Gnomad SAS exome AF: 0.0941

Gnomad FIN exome AF: 0.0902

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0332 AC: 46521 AN: 1402732 Hom.: 1540 Cov.: 31 AF XY: 0.0352 AC XY: 24392 AN XY: 693584

Gnomad4 AFR exome AF: 0.00387

Gnomad4 AMR exome AF: 0.0811

Gnomad4 ASJ exome AF: 0.0189

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0931

Gnomad4 FIN exome AF: 0.0931

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0353

GnomAD4 genome AF: 0.0329 AC: 5010 AN: 152280 Hom.: 169 Cov.: 33 AF XY: 0.0374 AC XY: 2783 AN XY: 74456

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.0476

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0875

Gnomad4 NFE AF: 0.0278

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0255 Hom.: 33

Bravo AF: 0.0259

Asia WGS AF: 0.101 AC: 351 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	10
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2228260; hg19: chr22-29196306; COSMIC: COSV53276792; COSMIC: COSV53276792;