chr22-28796168-C-T

Variant names:

• chr22-28796168-C-T
• rs751050496
• NM_001079539.2:c.478G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001079539.2(XBP1):​c.478G>A​(p.Gly160Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000837 in 1,434,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: XBP1 NM_001079539.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079539.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.478G>A	p.Gly160Arg	missense	Exon 4 of 6	NP_001073007.1	P17861-2
	XBP1	NM_001393999.1		c.328G>A	p.Gly110Arg	missense	Exon 4 of 6	NP_001380928.1
	XBP1	NM_005080.4		c.478G>A	p.Gly160Arg	missense	Exon 4 of 5	NP_005071.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	ENST00000344347.6	TSL:5 MANE Select	c.478G>A	p.Gly160Arg	missense	Exon 4 of 6	ENSP00000343155.5	P17861-2
	XBP1	ENST00000216037.10	TSL:1	c.478G>A	p.Gly160Arg	missense	Exon 4 of 5	ENSP00000216037.6	P17861-1
	XBP1	ENST00000403532.7	TSL:3	c.493G>A	p.Gly165Arg	missense	Exon 4 of 5	ENSP00000385162.3	B1AHH2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000459 AC: 1 AN: 218052 AF XY: 0.00000844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000991

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000837 AC: 12 AN: 1434484 Hom.: 0 Cov.: 31 AF XY: 0.00000842 AC XY: 6 AN XY: 712888

African (AFR) AF: 0.0000310 AC: 1 AN: 32230

American (AMR) AF: 0.00 AC: 0 AN: 39380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24234

East Asian (EAS) AF: 0.00 AC: 0 AN: 38704

South Asian (SAS) AF: 0.00 AC: 0 AN: 82276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1100376

Other (OTH) AF: 0.00 AC: 0 AN: 59088

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.012	D
Sift4G	Benign	0.25	T
Polyphen		0.83	P
Vest4		0.95
MutPred		0.51		Loss of sheet (P = 0.0037)
MVP		0.58
MPC		1.1
ClinPred		0.85	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.46
gMVP		0.36
Mutation Taster		=30/70	disease causing

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

Other links and lift over

dbSNP: rs751050496; hg19: chr22-29192156; COSMIC: COSV108031113; COSMIC: COSV108031113;