rs28989189

chr15-40170645-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001211.6(BUB1B):c.348T>C(p.Tyr116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00932 in 1,613,708 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (110 hom.)
• Consequence: BUB1B NM_001211.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.162

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 15-40170645-T-C is Benign according to our data. Variant chr15-40170645-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 238666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40170645-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.162 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00603 (918/152326) while in subpopulation NFE AF= 0.00966 (657/68030). AF 95% confidence interval is 0.00905. There are 4 homozygotes in gnomad4. There are 422 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.348T>C	p.Tyr116=	synonymous_variant	4/23	ENST00000287598.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.348T>C	p.Tyr116=	synonymous_variant	4/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes AF: 0.00602 AC: 917 AN: 152208 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00966

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00694 AC: 1745 AN: 251348 Hom.: 14 AF XY: 0.00727 AC XY: 987 AN XY: 135852

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00859

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.00961

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00967 AC: 14127 AN: 1461382 Hom.: 110 Cov.: 32 AF XY: 0.00961 AC XY: 6984 AN XY: 727022

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00794

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.0108

Gnomad4 OTH exome AF: 0.00919

GnomAD4 genome AF: 0.00603 AC: 918 AN: 152326 Hom.: 4 Cov.: 32 AF XY: 0.00566 AC XY: 422 AN XY: 74496

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00850

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00966

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00906 Hom.: 4

Bravo AF: 0.00583

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.0117

EpiControl AF: 0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	This variant is associated with the following publications: (PMID: 16182441) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BUB1B: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 05, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Colorectal cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Mosaic variegated aneuploidy syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.5
Dann	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs28989189; hg19: chr15-40462846; COSMIC: COSV104598933; COSMIC: COSV104598933;