Genetic Variant NM_001211.6:c.-347G>A (chr15-40160874-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001211.6(BUB1B):c.-347G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 299,910 control chromosomes in the GnomAD database, including 4,296 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 0.15 ( 1983 hom., cov: 33)

Exomes 𝑓: 0.16 ( 2313 hom. )

Consequence

BUB1B
NM_001211.6 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.67

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

mosaic variegated aneuploidy syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
mosaic variegated aneuploidy syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BUB1B links:

Genome browser will be placed here

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=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6 link	c.-347G>A		upstream_gene_variant		ENST00000287598.11	NP_001202.5	O60566-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11 link	c.-347G>A		upstream_gene_variant		1	NM_001211.6	ENSP00000287598.7		O60566-1
BUB1B	ENST00000412359.7 link	c.-347G>A		upstream_gene_variant		2		ENSP00000398470.3		O60566-3

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22538

AN:

152152

Hom.:

1984

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0775

Gnomad AMI

AF:

0.243

Gnomad AMR

AF:

0.110

Gnomad ASJ

AF:

0.200

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0689

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.128

GnomAD4 exome

AF:

0.158

AC:

23301

AN:

147640

Hom.:

2313

AF XY:

0.156

AC XY:

11487

AN XY:

73528

show subpopulations

African (AFR)

AF:

0.0764

AC:

431

AN:

5640

American (AMR)

AF:

0.0939

AC:

493

AN:

5250

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

1297

AN:

6554

East Asian (EAS)

AF:

0.00428

AC:

AN:

13782

South Asian (SAS)

AF:

0.0596

AC:

463

AN:

7764

European-Finnish (FIN)

AF:

0.223

AC:

1488

AN:

6664

Middle Eastern (MID)

AF:

0.135

AC:

103

AN:

762

European-Non Finnish (NFE)

AF:

0.190

AC:

17281

AN:

90862

Other (OTH)

AF:

0.163

AC:

1686

AN:

10362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

913

1826

2738

3651

4564

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.148

AC:

22533

AN:

152270

Hom.:

1983

Cov.:

AF XY:

0.146

AC XY:

10880

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0773

AC:

3215

AN:

41572

American (AMR)

AF:

0.110

AC:

1681

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.200

AC:

693

AN:

3470

East Asian (EAS)

AF:

0.00424

AC:

AN:

5190

South Asian (SAS)

AF:

0.0684

AC:

330

AN:

4826

European-Finnish (FIN)

AF:

0.241

AC:

2559

AN:

10600

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.199

AC:

13502

AN:

67998

Other (OTH)

AF:

0.127

AC:

267

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1006

2013

3019

4026

5032

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.154

Hom.:

424

Bravo

AF:

0.137

Asia WGS

AF:

0.0440

AC:

152

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.25

(source)

DANN

Benign

0.89

PhyloP100

-2.7

PromoterAI

-0.013

Neutral

(source)

Splicing

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

Publications

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NM_001211.6:c.-347G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over