rs1801376

chr15-40185630-G-A

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.1046G>A(p.Arg349Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 1,612,848 control chromosomes in the GnomAD database, including 385,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39490 hom., cov: 32)
  • Exomes 𝑓: 0.68 (346041 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 3.42

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.3588683E-7).
• BP6: Variant 15-40185630-G-A is Benign according to our data. Variant chr15-40185630-G-A is described in ClinVar as [Benign]. Clinvar id is 133780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40185630-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.1046G>A	p.Arg349Gln	missense_variant	8/23	ENST00000287598.11
LOC107984763	XR_001751506.2	n.218-5429C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.1046G>A	p.Arg349Gln	missense_variant	8/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108322 AN: 152044 Hom.: 39444 Cov.: 32

Gnomad AFR AF: 0.824

Gnomad AMI AF: 0.846

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.644

GnomAD3 exomes AF: 0.650 AC: 163454 AN: 251422 Hom.: 55071 AF XY: 0.645 AC XY: 87634 AN XY: 135882

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.611

Gnomad ASJ exome AF: 0.593

Gnomad EAS exome AF: 0.323

Gnomad SAS exome AF: 0.544

Gnomad FIN exome AF: 0.736

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.683 AC: 998301 AN: 1460684 Hom.: 346041 Cov.: 46 AF XY: 0.679 AC XY: 493532 AN XY: 726704

Gnomad4 AFR exome AF: 0.826

Gnomad4 AMR exome AF: 0.618

Gnomad4 ASJ exome AF: 0.586

Gnomad4 EAS exome AF: 0.350

Gnomad4 SAS exome AF: 0.549

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.706

Gnomad4 OTH exome AF: 0.658

GnomAD4 genome AF: 0.713 AC: 108435 AN: 152164 Hom.: 39490 Cov.: 32 AF XY: 0.706 AC XY: 52549 AN XY: 74398

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.596

Gnomad4 EAS AF: 0.329

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.739

Gnomad4 NFE AF: 0.707

Gnomad4 OTH AF: 0.647

Alfa AF: 0.695 Hom.: 95348

Bravo AF: 0.709

TwinsUK AF: 0.703 AC: 2607

ALSPAC AF: 0.703 AC: 2708

ESP6500AA AF: 0.814 AC: 3587

ESP6500EA AF: 0.696 AC: 5985

ExAC AF: 0.656 AC: 79710

Asia WGS AF: 0.483 AC: 1681 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.690

ClinVar

Significance: Benign

Submissions summary: Benign:3 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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	17
Dann	Benign	0.30
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	7.4e-7	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.2	N;N
REVEL	Benign	0.061
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.18
MPC		0.23
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.022
gMVP		0.062

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: rs1801376; hg19: chr15-40477831; COSMIC: COSV55009718; COSMIC: COSV55009718;