Variant 2-110638013-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_004336.5(BUB1):c.3209G>A(p.Arg1070His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,441,822 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: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

BUB1
NM_004336.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2601859).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000485 (7/1441822) while in subpopulation MID AF= 0.000539 (3/5566). AF 95% confidence interval is 0.000146. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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
BUB1	NM_004336.5 linkuse as main transcript	c.3209G>A	p.Arg1070His	missense_variant	25/25	ENST00000302759.11	NP_004327.1
BUB1	NM_001278616.2 linkuse as main transcript	c.3149G>A	p.Arg1050His	missense_variant	24/24		NP_001265545.1
BUB1	NM_001278617.2 linkuse as main transcript	c.3038G>A	p.Arg1013His	missense_variant	24/24		NP_001265546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1	ENST00000302759.11 linkuse as main transcript	c.3209G>A	p.Arg1070His	missense_variant	25/25	1	NM_004336.5	ENSP00000302530	P1	O43683-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000839

AC:

AN:

238474

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129060

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000328

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:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000485

AC:

AN:

1441822

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

716604

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000243

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.0000122

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2023

The p.R1070H variant (also known as c.3209G>A), located in coding exon 25 of the BUB1 gene, results from a G to A substitution at nucleotide position 3209. The arginine at codon 1070 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

.;.;T

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

.;.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.12

MutPred

0.58

.;.;Loss of MoRF binding (P = 0.0755);

MVP

0.79

MPC

0.51

ClinPred

0.74

GERP RS

5.0

Varity_R

0.32

gMVP

0.56

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over