15-40161239-G-A

Position:

• chr15-40161239-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001211.6(BUB1B):​c.19G>A​(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.157

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08481312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BUB1B	NM_001211.6	c.19G>A	p.Glu7Lys	missense_variant	1/23	ENST00000287598.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BUB1B	ENST00000287598.11	c.19G>A	p.Glu7Lys	missense_variant	1/23	1	NM_001211.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247274 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134004

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461072 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726746

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2024

The p.E7K variant (also known as c.19G>A), located in coding exon 1 of the BUB1B gene, results from a G to A substitution at nucleotide position 19. The glutamic acid at codon 7 is replaced by lysine, 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

Mosaic variegated aneuploidy syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 533915). This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 7 of the BUB1B protein (p.Glu7Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.022
Sift	Benign	0.034	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.29		Gain of MoRF binding (P = 7e-04);Gain of MoRF binding (P = 7e-04);
MVP		0.57
MPC		0.22
ClinPred		0.16	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1218056057; hg19: chr15-40453440;