rs767213728

chr15-40202608-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001211.6(BUB1B):c.1648C>T(p.Arg550Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R550R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BUB1B NM_001211.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.932

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 15-40202608-C-T is Pathogenic according to our data. Variant chr15-40202608-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 438799.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.1648C>T	p.Arg550Ter	stop_gained	14/23	ENST00000287598.11
LOC107984763	XR_001751506.2	n.218-22407G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.1648C>T	p.Arg550Ter	stop_gained	14/23	1	NM_001211.6	P1
BUB1B	ENST00000412359.7	c.1690C>T	p.Arg564Ter	stop_gained	14/23	2
BUB1B	ENST00000558972.1	n.453C>T		non_coding_transcript_exon_variant	4/5	3
BUB1B	ENST00000559733.5	c.*561C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.00000205 AC: 3 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 23, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438799). This premature translational stop signal has been observed in individual(s) with mosaic variegated aneuploidy (PMID: 28976722). This variant is present in population databases (rs767213728, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg550*) in the BUB1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BUB1B are known to be pathogenic (PMID: 15475955, 21190457). -
Pathogenic, no assertion criteria provided	research	Donald Williams Parsons Laboratory, Baylor College of Medicine	Apr 30, 2014	This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous, maternally inherited in a 7-year-old male with glioma; LOH was not detected in the tumor in this region. There was a paternal family history of cancer. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	35
Dann	Uncertain	0.98
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.062	N
MutationTaster	Benign	1.0	A;A
Vest4		0.70
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs767213728; hg19: chr15-40494809; COSMIC: COSV99806582; COSMIC: COSV99806582;