Genetic Variant NM_004336.5:c.1218-544A>G (chr2-110660580-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004336.5(BUB1):c.1218-544A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00809 in 152,260 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0081 ( 75 hom., cov: 32)

Consequence

BUB1
NM_004336.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.105

Publications

2 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
mosaic variegated aneuploidy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, ClinGen
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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
BUB1	NM_004336.5 link	c.1218-544A>G	intron_variant	Intron 10 of 24	ENST00000302759.11	NP_004327.1
BUB1	NM_001278616.2 link	c.1158-544A>G	intron_variant	Intron 9 of 23		NP_001265545.1
BUB1	NM_001278617.2 link	c.1218-544A>G	intron_variant	Intron 10 of 23		NP_001265546.1
BUB1	XM_047445616.1 link	c.1218-544A>G	intron_variant	Intron 10 of 20		XP_047301572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1	ENST00000302759.11 link	c.1218-544A>G		intron_variant	Intron 10 of 24	1	NM_004336.5	ENSP00000302530.6

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1237

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.169

Gnomad SAS

AF:

0.0340

Gnomad FIN

AF:

0.00613

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.00956

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00809

AC:

1232

AN:

152260

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

733

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41562

American (AMR)

AF:

0.00118

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.168

AC:

871

AN:

5174

South Asian (SAS)

AF:

0.0340

AC:

164

AN:

4818

European-Finnish (FIN)

AF:

0.00613

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68022

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.0880

AC:

306

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

7.2

(source)

DANN

Benign

0.73

PhyloP100

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over