rs28989187

Positions:

• chr15-40202609-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001211.6(BUB1B):​c.1649G>A​(p.Arg550Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,613,904 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R550R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (8 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:2 O:1
• Conservation: PhyloP100: -0.159

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=0.03298241).
• BP6: Variant 15-40202609-G-A is Benign according to our data. Variant chr15-40202609-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 6766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40202609-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000723 (110/152084) while in subpopulation EAS AF= 0.0209 (108/5178). AF 95% confidence interval is 0.0177. There are 0 homozygotes in gnomad4. There are 63 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.1649G>A	p.Arg550Gln	missense_variant	14/23	ENST00000287598.11
LOC107984763	XR_001751506.2	n.218-22408C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.1649G>A	p.Arg550Gln	missense_variant	14/23	1	NM_001211.6	P1
BUB1B	ENST00000412359.7	c.1691G>A	p.Arg564Gln	missense_variant	14/23	2
BUB1B	ENST00000558972.1	n.454G>A		non_coding_transcript_exon_variant	4/5	3
BUB1B	ENST00000559733.5	c.*562G>A		3_prime_UTR_variant, NMD_transcript_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.000724 AC: 110 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00165 AC: 414 AN: 251474 Hom.: 4 AF XY: 0.00148 AC XY: 201 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000348 AC: 508 AN: 1461820 Hom.: 8 Cov.: 32 AF XY: 0.000320 AC XY: 233 AN XY: 727212

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0115

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000504 Hom.: 0

Bravo AF: 0.000805

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1 Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Premature chromatid separation trait Other:1

Affects, no assertion criteria provided

literature only

OMIM

Nov 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0090
DANN	Benign	0.38
DEOGEN2	Benign	0.066	T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.7e-12	A;A
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.016
Sift	Benign	1.0	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0010	B;B
Vest4		0.058
MVP		0.62
MPC		0.23
ClinPred		0.0087	T
GERP RS		-10
Varity_R		0.012
gMVP		0.26

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: rs28989187; hg19: chr15-40494810; COSMIC: COSV99807163; COSMIC: COSV99807163;