chr15-40200320-C-T

Position:

chr15-40200320-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001211.6(BUB1B):c.1478C>T(p.Thr493Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

BUB1B
NM_001211.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 0.177

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:

BUB1B (HGNC:):

BUB1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.065768).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000168 (245/1461636) while in subpopulation MID AF= 0.000867 (5/5764). AF 95% confidence interval is 0.000341. There are 0 homozygotes in gnomad4_exome. There are 123 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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	Protein	UniProt
BUB1B	NM_001211.6 linkuse as main transcript	c.1478C>T	p.Thr493Ile	missense_variant	11/23	ENST00000287598.11	NP_001202.5	O60566-1
LOC107984763	XR_001751506.2 linkuse as main transcript	n.218-20119G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11 linkuse as main transcript	c.1478C>T	p.Thr493Ile	missense_variant	11/23	1	NM_001211.6	ENSP00000287598.7		O60566-1
BUB1B	ENST00000412359.7 linkuse as main transcript	c.1520C>T	p.Thr507Ile	missense_variant	11/23	2		ENSP00000398470.3		O60566-3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251274

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

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:

0.000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461636

Hom.:

Cov.:

AF XY:

0.000169

AC XY:

123

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carcinoma of colon;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

Oct 31, 2018

- -

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

May 15, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27331020, 24728327) -

Mosaic variegated aneuploidy syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 493 of the BUB1B protein (p.Thr493Ile). This variant is present in population databases (rs146795655, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 133767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.37

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.048

Sift

Benign

0.22

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0010

B;B

Vest4

0.16

MVP

0.74

MPC

0.21

ClinPred

0.016

GERP RS

0.62

Varity_R

0.028

gMVP

0.19

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