22-28800345-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001079539.2(XBP1):c.180G>C(p.Lys60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K60T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: XBP1 NM_001079539.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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/exons	MANE	UniProt
XBP1	NM_001079539.2	c.180G>C	p.Lys60Asn	missense_variant	1/6	ENST00000344347.6
XBP1	NM_005080.4	c.180G>C	p.Lys60Asn	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.180G>C	p.Lys60Asn	missense_variant	1/6	5	NM_001079539.2	P4
XBP1	ENST00000216037.10	c.180G>C	p.Lys60Asn	missense_variant	1/5	1		A2
XBP1	ENST00000403532.7	c.180G>C	p.Lys60Asn	missense_variant	1/5	3		A2
XBP1	ENST00000482720.1	n.225G>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Aug 02, 2023

The c.180G>C (p.K60N) alteration is located in exon 1 (coding exon 1) of the XBP1 gene. This alteration results from a G to C substitution at nucleotide position 180, causing the lysine (K) at amino acid position 60 to be replaced by an asparagine (N). 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	0.99
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.5	D;D;.;D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.60
MutPred		0.34		Loss of methylation at K60 (P = 0.0084);Loss of methylation at K60 (P = 0.0084);Loss of methylation at K60 (P = 0.0084);Loss of methylation at K60 (P = 0.0084);
MVP		0.37
MPC		1.1
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.85
gMVP		0.78

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: rs566044389; hg19: chr22-29196333;