rs778590557

chr15-40196653-TGAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_SupportingBS1_Supporting

The NM_001211.6(BUB1B):c.1171_1173del(p.Glu391del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,613,974 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 2 hom. )

Consequence

BUB1B
NM_001211.6 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 3.43

Variant links:

Genes affected

BUB1B (HGNC:1149): (BUB1 mitotic checkpoint serine/threonine kinase B) This gene encodes a kinase involved in spindle checkpoint function. The protein has been localized to the kinetochore and plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Impaired spindle checkpoint function has been found in many forms of cancer. [provided by RefSeq, Jul 2008]

BUB1B links:

LOC107984763 (HGNC:):

LOC107984763 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001211.6. Strenght limited to Supporting due to length of the change: 1aa.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000361 (55/152210) while in subpopulation NFE AF= 0.000647 (44/68012). AF 95% confidence interval is 0.000495. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6 linkuse as main transcript	c.1171_1173del	p.Glu391del	inframe_deletion	9/23	ENST00000287598.11
LOC107984763	XR_001751506.2 linkuse as main transcript	n.218-16455_218-16453del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11 linkuse as main transcript	c.1171_1173del	p.Glu391del	inframe_deletion	9/23	1	NM_001211.6	P1	O60566-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000354

AC:

AN:

251240

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000636

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:

0.000564

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000618

AC:

903

AN:

1461764

Hom.:

AF XY:

0.000611

AC XY:

444

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000648

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:

0.000755

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000361

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.000434

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Mosaic variegated aneuploidy syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This variant, c.1171_1173del, results in the deletion of 1 amino acid(s) of the BUB1B protein (p.Glu391del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs778590557, gnomAD 0.06%). This variant has been observed in individual(s) with colorectal cancer (PMID: 27239782). This variant is also known as p.Glu390del. ClinVar contains an entry for this variant (Variation ID: 403741). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 13, 2023	The BUB1B c.1171_1173del (p.Glu391del) change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The change results in the deletion of a single glutamic acid residue in the BUB3-binding domain. Functional studies indicate that this variant does not affect binding to the spindle assembly checkpoint proteins BUB1 and BUB3 (PMID: 27239782). This variant has been reported in an individual with colorectal cancer (PMID: 27239782). This variant is also known as p.Glu390del in the literature. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

The c.1171_1173delGAG (p.E391del) alteration is located in exon 9 (coding exon 9) of the BUB1B gene. This alteration consists of an in-frame deletion of 3 nucleotides between nucleotide positions c.1171 and c.1173, resulting in the deletion of 1 residue. This variant was detected in two siblings who had early-onset colorectal cancer and breast cancer (<50y); however, it was also detected in their unaffected brother, and in healthy control individuals (Hahn, 2016). Experimental studies showed no significant difference in the binding of BUB1 or BUB3 to BUBR1 between this alteration and wild type (Hahn, 2016). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Colorectal cancer;C1850343:Mosaic variegated aneuploidy syndrome 1;C1864389:Premature chromatid separation trait

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over