rs202108787

Positions:

• chr15-40210214-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001211.6(BUB1B):​c.2385+4G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,577,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: BUB1B NM_001211.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00006112
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000451 (643/1425668) while in subpopulation NFE AF= 0.000577 (623/1079566). AF 95% confidence interval is 0.000539. There are 0 homozygotes in gnomad4_exome. There are 307 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.2385+4G>C		splice_donor_region_variant, intron_variant		ENST00000287598.11	NP_001202.5
LOC107984763	XR_001751506.2	n.217+29271C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.2385+4G>C		splice_donor_region_variant, intron_variant		1	NM_001211.6	ENSP00000287598	P1
BUB1B	ENST00000412359.7	c.2427+4G>C		splice_donor_region_variant, intron_variant		2		ENSP00000398470

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 14 AN: 151638 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000923 AC: 23 AN: 249128 Hom.: 0 AF XY: 0.0000815 AC XY: 11 AN XY: 135032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000451 AC: 643 AN: 1425668 Hom.: 0 Cov.: 29 AF XY: 0.000432 AC XY: 307 AN XY: 711450

Gnomad4 AFR exome AF: 0.0000919

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000577

Gnomad4 OTH exome AF: 0.000236

GnomAD4 genome AF: 0.0000923 AC: 14 AN: 151638 Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6 AN XY: 74036

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000136

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 238663). This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. This variant is present in population databases (rs202108787, gnomAD 0.02%). This sequence change falls in intron 18 of the BUB1B gene. It does not directly change the encoded amino acid sequence of the BUB1B protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.018
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: rs202108787; hg19: chr15-40502415; COSMIC: COSV104598952; COSMIC: COSV104598952;