22-28800510-T-TGCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001079539.2(XBP1):c.14_15insGGC(p.Ala6dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00498 in 1,490,232 control chromosomes in the GnomAD database, including 32 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (20 hom.)
• Consequence: XBP1 NM_001079539.2 inframe_insertion
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.69

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001079539.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 22-28800510-T-TGCC is Benign according to our data. Variant chr22-28800510-T-TGCC is described in ClinVar as [Likely_benign]. Clinvar id is 1255618.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00867 (1318/152078) while in subpopulation AFR AF= 0.0225 (929/41370). AF 95% confidence interval is 0.0213. There are 12 homozygotes in gnomad4. There are 597 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XBP1	NM_001079539.2	c.14_15insGGC	p.Ala6dup	inframe_insertion	1/6	ENST00000344347.6
XBP1	NM_005080.4	c.14_15insGGC	p.Ala6dup	inframe_insertion	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.14_15insGGC	p.Ala6dup	inframe_insertion	1/6	5	NM_001079539.2	P4
XBP1	ENST00000216037.10	c.14_15insGGC	p.Ala6dup	inframe_insertion	1/5	1		A2
XBP1	ENST00000403532.7	c.14_15insGGC	p.Ala6dup	inframe_insertion	1/5	3		A2
XBP1	ENST00000482720.1	n.59_60insGGC		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00861 AC: 1308 AN: 151970 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00440

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00241 AC: 211 AN: 87436 Hom.: 0 AF XY: 0.00219 AC XY: 111 AN XY: 50732

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.00224

Gnomad FIN exome AF: 0.000676

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00455

GnomAD4 exome AF: 0.00456 AC: 6106 AN: 1338154 Hom.: 20 Cov.: 32 AF XY: 0.00442 AC XY: 2920 AN XY: 661066

Gnomad4 AFR exome AF: 0.0233

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.000347

Gnomad4 EAS exome AF: 0.000498

Gnomad4 SAS exome AF: 0.00252

Gnomad4 FIN exome AF: 0.000462

Gnomad4 NFE exome AF: 0.00462

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.00867 AC: 1318 AN: 152078 Hom.: 12 Cov.: 33 AF XY: 0.00803 AC XY: 597 AN XY: 74374

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00492 Hom.: 2

Bravo AF: 0.00985

Asia WGS AF: 0.00203 AC: 7 AN: 3468

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant polycystic liver disease Benign:1

Likely benign, no assertion criteria provided

research

Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center

Sep 01, 2021

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs528996789; hg19: chr22-29196498;