22-28796168-C-T

Variant names:

• chr22-28796168-C-T
• rs751050496
• ENST00000344347.6:c.478G>A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.478G>A	p.Gly160Arg	missense_variant	Exon 4 of 6		NP_001073007.1
XBP1	NM_001393999.1	c.328G>A	p.Gly110Arg	missense_variant	Exon 4 of 6		NP_001380928.1
XBP1	NM_005080.4	c.478G>A	p.Gly160Arg	missense_variant	Exon 4 of 5		NP_005071.2
XBP1	NM_001394000.1	c.328G>A	p.Gly110Arg	missense_variant	Exon 4 of 5		NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.478G>A	p.Gly160Arg	missense_variant	Exon 4 of 6	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000459 AC: 1 AN: 218052 Hom.: 0 AF XY: 0.00000844 AC XY: 1 AN XY: 118436

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 SAS 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

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.478G>A (p.G160R) alteration is located in exon 4 (coding exon 4) of the XBP1 gene. This alteration results from a G to A substitution at nucleotide position 478, causing the glycine (G) at amino acid position 160 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;.
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;.;L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	D;N;.;D;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.012	D;D;.;T;T
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		0.83, 0.73	.;.;P;P;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

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: rs751050496; hg19: chr22-29192156;