22-28795581-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079539.2(XBP1):c.725C>T(p.Thr242Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: XBP1 NM_001079539.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35182363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XBP1	NM_001079539.2	c.725C>T	p.Thr242Met	missense_variant	6/6	ENST00000344347.6
XBP1	NM_001393999.1	c.575C>T	p.Thr192Met	missense_variant	6/6
XBP1	NM_005080.4	c.751C>T	p.Arg251Cys	missense_variant	5/5
XBP1	NM_001394000.1	c.601C>T	p.Arg201Cys	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.725C>T	p.Thr242Met	missense_variant	6/6	5	NM_001079539.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74432

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.751C>T (p.R251C) alteration is located in exon 5 (coding exon 5) of the XBP1 gene. This alteration results from a C to T substitution at nucleotide position 751, causing the arginine (R) at amino acid position 251 to be replaced by a cysteine (C). 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	Benign	0.13
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.28
MutPred		0.38		.;.;Loss of MoRF binding (P = 2e-04);
MVP		0.64
MPC		0.84
ClinPred		0.95	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.27

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: rs947050650; hg19: chr22-29191569;