rs946027171

chr15-40176483-T-G

Variant summary

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

The NM_001211.6(BUB1B):c.391T>G(p.Leu131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.57

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]

LOC107984763 (HGNC:):

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=0.26698372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.391T>G	p.Leu131Val	missense_variant	5/23	ENST00000287598.11
LOC107984763	XR_001751506.2	n.392-1999A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.391T>G	p.Leu131Val	missense_variant	5/23	1	NM_001211.6	P1
BUB1B	ENST00000412359.7	c.433T>G	p.Leu145Val	missense_variant	5/23	2
BUB1B	ENST00000559414.5	n.459T>G		non_coding_transcript_exon_variant	5/5	4
BUB1B	ENST00000560120.5	n.445T>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251428 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The p.L131V variant (also known as c.391T>G), located in coding exon 5 of the BUB1B gene, results from a T to G substitution at nucleotide position 391. The leucine at codon 131 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mosaic variegated aneuploidy syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 01, 2017

This sequence change replaces leucine with valine at codon 131 of the BUB1B protein (p.Leu131Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BUB1B-related disease. ClinVar contains an entry for this variant (Variation ID: 403739). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	17
Dann	Benign	0.97
DEOGEN2	Benign	0.092	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.15
Sift	Benign	0.18	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.072	B;.
Vest4		0.28
MutPred		0.70		Gain of MoRF binding (P = 0.0843);.;
MVP		0.78
MPC		0.26
ClinPred		0.13	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.41

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: rs946027171; hg19: chr15-40468684;