15-40185630-G-A

Variant names:

• chr15-40185630-G-A
• rs1801376
• NM_001211.6:c.1046G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:4 O:1
• Conservation: PhyloP100: 3.42
• Publications: 66 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: Benign. The variant received -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 VariationId is 133780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001211.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	NM_001211.6	MANE Select	c.1046G>A	p.Arg349Gln	missense	Exon 8 of 23	NP_001202.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.1046G>A	p.Arg349Gln	missense	Exon 8 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.1088G>A	p.Arg363Gln	missense	Exon 8 of 23	ENSP00000398470.3
	BUB1B	ENST00000557848.1	TSL:3	n.305G>A		non_coding_transcript_exon	Exon 1 of 3

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

GnomAD2 exomes AF: 0.650 AC: 163454 AN: 251422 AF XY: 0.645

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 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

African (AFR) AF: 0.826 AC: 27635 AN: 33462

American (AMR) AF: 0.618 AC: 27643 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 15324 AN: 26128

East Asian (EAS) AF: 0.350 AC: 13885 AN: 39698

South Asian (SAS) AF: 0.549 AC: 47368 AN: 86244

European-Finnish (FIN) AF: 0.733 AC: 39141 AN: 53396

Middle Eastern (MID) AF: 0.543 AC: 3128 AN: 5756

European-Non Finnish (NFE) AF: 0.706 AC: 784468 AN: 1110920

Other (OTH) AF: 0.658 AC: 39709 AN: 60362

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

African (AFR) AF: 0.824 AC: 34232 AN: 41528

American (AMR) AF: 0.629 AC: 9611 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2068 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1697 AN: 5164

South Asian (SAS) AF: 0.547 AC: 2636 AN: 4816

European-Finnish (FIN) AF: 0.739 AC: 7831 AN: 10592

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48051 AN: 67996

Other (OTH) AF: 0.647 AC: 1367 AN: 2112

Alfa AF: 0.699 Hom.: 145882

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	7.4e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N
PhyloP100		3.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MPC		0.23
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.022
gMVP		0.062
Mutation Taster		=99/1	polymorphism (auto)

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