rs28989189

Variant names:

• chr15-40170645-T-C
• rs28989189
• NM_001211.6:c.348T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001211.6(BUB1B):​c.348T>C​(p.Tyr116Tyr) 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:8
• Conservation: PhyloP100: 0.162
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 238666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.348T>C	p.Tyr116Tyr	synonymous	Exon 4 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.348T>C	p.Tyr116Tyr	synonymous	Exon 4 of 23	ENSP00000287598.7
	BUB1B	ENST00000412359.7	TSL:2	c.390T>C	p.Tyr130Tyr	synonymous	Exon 4 of 23	ENSP00000398470.3
	BUB1B	ENST00000560120.5	TSL:3	n.402T>C		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes AF: 0.00694 AC: 1745 AN: 251348 AF XY: 0.00727

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 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

African (AFR) AF: 0.00146 AC: 49 AN: 33462

American (AMR) AF: 0.00356 AC: 159 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0137 AC: 359 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.00794 AC: 685 AN: 86244

European-Finnish (FIN) AF: 0.00375 AC: 200 AN: 53382

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5762

European-Non Finnish (NFE) AF: 0.0108 AC: 12040 AN: 1111684

Other (OTH) AF: 0.00919 AC: 555 AN: 60374

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

African (AFR) AF: 0.00195 AC: 81 AN: 41582

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00966 AC: 657 AN: 68030

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00923 Hom.: 5

Bravo AF: 0.00583

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.0117

EpiControl AF: 0.0114

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Colorectal cancer (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mosaic variegated aneuploidy syndrome 1 (1)
-	-	1	not specified (1)
-	-	1	Premature chromatid separation trait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.5
DANN	Benign	0.39
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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