Genetic Variant BUB1:c.422+1G>T (chr2-110672660-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_004336.5(BUB1):c.422+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000702 in 1,424,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

BUB1
NM_004336.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.91

Publications

0 publications found

Variant links:

Genes affected

BUB1 (HGNC:1148): (BUB1 mitotic checkpoint serine/threonine kinase) This gene encodes a serine/threonine-protein kinase that play a central role in mitosis. The encoded protein functions in part by phosphorylating members of the mitotic checkpoint complex and activating the spindle checkpoint. This protein also plays a role in inhibiting the activation of the anaphase promoting complex/cyclosome. This protein may also function in the DNA damage response. Mutations in this gene have been associated with aneuploidy and several forms of cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

BUB1 Gene-Disease associations (from GenCC):

microcephaly 30, primary, autosomal recessive
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
mosaic variegated aneuploidy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen, Ambry Genetics
familial colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BUB1 links:

ENSG00000289202 (HGNC:):

ENSG00000289202 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004336.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BUB1	NM_004336.5	MANE Select	c.422+1G>T	splice_donor intron	N/A	NP_004327.1	O43683-1
BUB1	NM_001278616.2		c.362+1G>T	splice_donor intron	N/A	NP_001265545.1	O43683-3
BUB1	NM_001278617.2		c.422+1G>T	splice_donor intron	N/A	NP_001265546.1	O43683-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BUB1	ENST00000302759.11	TSL:1 MANE Select	c.422+1G>T	splice_donor intron	N/A	ENSP00000302530.6	O43683-1
BUB1	ENST00000409311.5	TSL:1	c.422+1G>T	splice_donor intron	N/A	ENSP00000386701.1	O43683-2
BUB1	ENST00000466333.5	TSL:1	n.455+1G>T	splice_donor intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.02e-7

AC:

AN:

1424554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31914

American (AMR)

AF:

0.00

AC:

AN:

36998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23812

East Asian (EAS)

AF:

0.00

AC:

AN:

39304

South Asian (SAS)

AF:

0.00

AC:

AN:

80634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5576

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094886

Other (OTH)

AF:

0.00

AC:

AN:

58744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.9

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.71

Position offset: 2

DS_DL_spliceai

0.99

Position offset: 1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over