rs1060499948

Variant names:

• chr15-40212527-T-C
• rs1060499948
• NM_001211.6:c.2414T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001211.6(BUB1B):​c.2414T>C​(p.Phe805Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. F805L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.89
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• mosaic variegated aneuploidy syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• mosaic variegated aneuploidy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107984763 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.2414T>C	p.Phe805Ser	missense_variant	Exon 19 of 23	ENST00000287598.11	NP_001202.5
LOC107984763	XR_001751506.2	n.217+26958A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.2414T>C	p.Phe805Ser	missense_variant	Exon 19 of 23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.2456T>C	p.Phe819Ser	missense_variant	Exon 19 of 23	2		ENSP00000398470.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F805S variant (also known as c.2414T>C), located in coding exon 19 of the BUB1B gene, results from a T to C substitution at nucleotide position 2414. The phenylalanine at codon 805 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mosaic variegated aneuploidy syndrome 1 Uncertain:1

Jun 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine with serine at codon 805 of the BUB1B protein (p.Phe805Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BUB1B-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;.
PhyloP100		3.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.95	P;.
Vest4		0.74
MutPred		0.54		Loss of stability (P = 0.0519);.;
MVP		0.84
MPC		0.94
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.43
gMVP		0.67

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

Other links and lift over

dbSNP: rs1060499948; hg19: chr15-40504728;