NM_001211.6:c.-115A>G

Variant names:

• chr15-40161106-A-G
• rs2277559
• NM_001211.6:c.-115A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001211.6(BUB1B):​c.-115A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 1,370,822 control chromosomes in the GnomAD database, including 326,613 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.70 (37473 hom., cov: 31)
  • Exomes 𝑓: 0.68 (289140 hom.)
• Consequence: BUB1B NM_001211.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.465
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.-115A>G		5_prime_UTR_variant	Exon 1 of 23	ENST00000287598.11	NP_001202.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.-115A>G		5_prime_UTR_variant	Exon 1 of 23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.-115A>G		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000398470.3

Frequencies

GnomAD3 genomes AF: 0.696 AC: 105749 AN: 151926 Hom.: 37437 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.596

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.634

GnomAD4 exome AF: 0.684 AC: 833242 AN: 1218774 Hom.: 289140 Cov.: 16 AF XY: 0.680 AC XY: 409646 AN XY: 602562

African (AFR) AF: 0.758 AC: 20676 AN: 27272

American (AMR) AF: 0.617 AC: 18794 AN: 30450

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 12243 AN: 20920

East Asian (EAS) AF: 0.354 AC: 12024 AN: 33968

South Asian (SAS) AF: 0.570 AC: 39355 AN: 69060

European-Finnish (FIN) AF: 0.733 AC: 34737 AN: 47390

Middle Eastern (MID) AF: 0.545 AC: 2838 AN: 5208

European-Non Finnish (NFE) AF: 0.706 AC: 659004 AN: 933238

Other (OTH) AF: 0.655 AC: 33571 AN: 51268

GnomAD4 genome AF: 0.696 AC: 105853 AN: 152048 Hom.: 37473 Cov.: 31 AF XY: 0.691 AC XY: 51360 AN XY: 74296

African (AFR) AF: 0.763 AC: 31677 AN: 41492

American (AMR) AF: 0.625 AC: 9547 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.596 AC: 2067 AN: 3470

East Asian (EAS) AF: 0.329 AC: 1696 AN: 5154

South Asian (SAS) AF: 0.566 AC: 2727 AN: 4816

European-Finnish (FIN) AF: 0.739 AC: 7798 AN: 10554

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48052 AN: 67972

Other (OTH) AF: 0.637 AC: 1347 AN: 2114

Alfa AF: 0.701 Hom.: 22539

Bravo AF: 0.690

Asia WGS AF: 0.493 AC: 1714 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	10
DANN	Benign	0.59
PhyloP100		0.47
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs2277559; hg19: chr15-40453307; COSMIC: COSV55012895;