15-40202590-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001211.6(BUB1B):c.1630C>T(p.Pro544Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

BUB1B
NM_001211.6 missense, splice_region

Scores

Splicing: ADA: 0.003889

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.209

Variant links:

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 links:

LOC107984763 (HGNC:):

LOC107984763 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.060026973).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000213 (312/1461646) while in subpopulation NFE AF= 0.000273 (303/1111808). AF 95% confidence interval is 0.000247. There are 0 homozygotes in gnomad4_exome. There are 150 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
BUB1B	NM_001211.6 link	c.1630C>T	p.Pro544Ser	missense_variant, splice_region_variant	Exon 14 of 23	ENST00000287598.11	NP_001202.5	O60566-1
LOC107984763	XR_001751506.2 link	n.218-22389G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11 link	c.1630C>T	p.Pro544Ser	missense_variant, splice_region_variant	Exon 14 of 23	1	NM_001211.6	ENSP00000287598.7		O60566-1
BUB1B	ENST00000412359.7 link	c.1672C>T	p.Pro558Ser	missense_variant, splice_region_variant	Exon 14 of 23	2		ENSP00000398470.3		O60566-3

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251466

Hom.:

AF XY:

0.0000809

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000213

AC:

312

AN:

1461646

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

150

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.000273

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000105

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.0000725

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:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000173

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mosaic variegated aneuploidy syndrome 1

Uncertain:2

Sep 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mosaic variegated aneuploidy syndrome 1 (MIM#257300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant as been reported as likely benign (LOVD) and as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 544 of the BUB1B protein (p.Pro544Ser). This variant is present in population databases (rs138332995, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 238662). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Carcinoma of colon;C1850343:Mosaic variegated aneuploidy syndrome 1;C1864389:Premature chromatid separation trait

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P544S variant (also known as c.1630C>T), located in coding exon 14 of the BUB1B gene, results from a C to T substitution at nucleotide position 1630. The proline at codon 544 is replaced by serine, an amino acid with 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. -

not provided

Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BUB1B p.Pro544Ser variant was not identified in the literature but was identified in dbSNP (ID: rs138332995) and ClinVar (classified as uncertain significance by Invitae and Fulgent Genetics). The variant was identified in control databases in 20 of 268202 chromosomes at a frequency of 0.00007457 (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: European (non-Finnish) in 19 of 118100 chromosomes (freq: 0.000161) and African in 1 of 23590 chromosomes (freq: 0.000042), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Pro544 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.060

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.36

N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.069

Sift

Benign

0.14

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.18

B;B

Vest4

0.11

MVP

0.78

MPC

0.20

ClinPred

0.062

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0039

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.050

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