rs146387899

Positions:

chr15-40185185-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_001211.6(BUB1B):c.772C>T(p.Leu258Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

BUB1B
NM_001211.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.409

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068919063).

BP6

Variant 15-40185185-C-T is Benign according to our data. Variant chr15-40185185-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 403745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000769 (117/152200) while in subpopulation AFR AF= 0.00262 (109/41536). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BUB1B	NM_001211.6 linkuse as main transcript	c.772C>T	p.Leu258Phe	missense_variant	7/23	ENST00000287598.11	NP_001202.5	O60566-1
LOC107984763	XR_001751506.2 linkuse as main transcript	n.218-4984G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BUB1B	ENST00000287598.11 linkuse as main transcript	c.772C>T	p.Leu258Phe	missense_variant	7/23	1	NM_001211.6	ENSP00000287598.7	O60566-1
BUB1B	ENST00000412359.7 linkuse as main transcript	c.814C>T	p.Leu272Phe	missense_variant	7/23	2		ENSP00000398470.3	O60566-3
BUB1B	ENST00000559461.1 linkuse as main transcript	n.181C>T		non_coding_transcript_exon_variant	2/2	2
BUB1B	ENST00000559733.5 linkuse as main transcript	n.169+1302C>T		intron_variant		3		ENSP00000453643.1	H0YMK5

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251020

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00262

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00272

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000769

AC:

117

AN:

152200

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00262

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000861

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

BUB1B-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Mosaic variegated aneuploidy syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.0069

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.028

Sift

Benign

0.25

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.074

B;B

Vest4

0.085

MVP

0.71

MPC

0.22

ClinPred

0.011

GERP RS

3.1

Varity_R

0.13

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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