chr15-40160874-G-A

Variant names:

• chr15-40160874-G-A
• rs3759843
• NM_001211.6:c.-347G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001211.6(BUB1B):​c.-347G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 299,910 control chromosomes in the GnomAD database, including 4,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1983 hom., cov: 33)
  • Exomes 𝑓: 0.16 (2313 hom.)
• Consequence: BUB1B NM_001211.6 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.67
• Publications: 6 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 15-40160874-G-A is Benign according to our data. Variant chr15-40160874-G-A is described in ClinVar as Benign. ClinVar VariationId is 1289187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	NM_001211.6	MANE Select	c.-347G>A		upstream_gene	N/A	NP_001202.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUB1B	ENST00000287598.11	TSL:1 MANE Select	c.-347G>A		upstream_gene	N/A	ENSP00000287598.7	O60566-1
	BUB1B	ENST00000412359.7	TSL:2	c.-347G>A		upstream_gene	N/A	ENSP00000398470.3	O60566-3
	BUB1B	ENST00000918306.1		c.-347G>A		upstream_gene	N/A	ENSP00000588365.1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22538 AN: 152152 Hom.: 1984 Cov.: 33

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.158 AC: 23301 AN: 147640 Hom.: 2313 AF XY: 0.156 AC XY: 11487 AN XY: 73528

African (AFR) AF: 0.0764 AC: 431 AN: 5640

American (AMR) AF: 0.0939 AC: 493 AN: 5250

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 1297 AN: 6554

East Asian (EAS) AF: 0.00428 AC: 59 AN: 13782

South Asian (SAS) AF: 0.0596 AC: 463 AN: 7764

European-Finnish (FIN) AF: 0.223 AC: 1488 AN: 6664

Middle Eastern (MID) AF: 0.135 AC: 103 AN: 762

European-Non Finnish (NFE) AF: 0.190 AC: 17281 AN: 90862

Other (OTH) AF: 0.163 AC: 1686 AN: 10362

GnomAD4 genome AF: 0.148 AC: 22533 AN: 152270 Hom.: 1983 Cov.: 33 AF XY: 0.146 AC XY: 10880 AN XY: 74452

African (AFR) AF: 0.0773 AC: 3215 AN: 41572

American (AMR) AF: 0.110 AC: 1681 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 693 AN: 3470

East Asian (EAS) AF: 0.00424 AC: 22 AN: 5190

South Asian (SAS) AF: 0.0684 AC: 330 AN: 4826

European-Finnish (FIN) AF: 0.241 AC: 2559 AN: 10600

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13502 AN: 67998

Other (OTH) AF: 0.127 AC: 267 AN: 2104

Alfa AF: 0.154 Hom.: 424

Bravo AF: 0.137

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.25
DANN	Benign	0.89
PhyloP100		-2.7
PromoterAI		-0.013	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3759843; hg19: chr15-40453075;