rs56079734

chr15-40165136-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001211.6(BUB1B):c.119C>T(p.Thr40Met) variant causes a missense change. The variant allele was found at a frequency of 0.0039 in 1,614,136 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T40A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (117 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5 O:1
• Conservation: PhyloP100: 4.26

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004684001).
• BP6: Variant 15-40165136-C-T is Benign according to our data. Variant chr15-40165136-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 6758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40165136-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.119C>T	p.Thr40Met	missense_variant	2/23	ENST00000287598.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.119C>T	p.Thr40Met	missense_variant	2/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3252 AN: 152134 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

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: 0.000132

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00532 AC: 1339 AN: 251492 Hom.: 55 AF XY: 0.00415 AC XY: 564 AN XY: 135922

Gnomad AFR exome AF: 0.0752

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00208 AC: 3043 AN: 1461884 Hom.: 117 Cov.: 31 AF XY: 0.00174 AC XY: 1262 AN XY: 727246

Gnomad4 AFR exome AF: 0.0760

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.0214 AC: 3258 AN: 152252 Hom.: 113 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74438

Gnomad4 AFR AF: 0.0750

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00399 Hom.: 35

Bravo AF: 0.0242

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00659 AC: 800

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2018	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 19, 1998

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2019

This variant is associated with the following publications: (PMID: 28767289, 27331020, 9521327, 24728327) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.3	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.42
MVP		0.85
MPC		0.77
ClinPred		0.022	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.24

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: rs56079734; hg19: chr15-40457337; COSMIC: COSV104598974;