15-40217525-A-G

Variant names:

• chr15-40217525-A-G
• rs1595538965
• NM_001211.6:c.2708A>G

Variant summary

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

The NM_001211.6(BUB1B):​c.2708A>G​(p.Asn903Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.12

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-PAK6 (HGNC:52276): (BUB1B-PAK6 readthrough) This gene represents readthrough transcription between the genes BUB1B (mitotic checkpoint serine/threonine-protein kinase BUB1 beta) and PAK6 (serine/threonine-protein kinase PAK 6). The protein encoded by the readthrough transcripts is the same as the product of the downstream gene (PAK6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

PAK6 (HGNC:16061): (p21 (RAC1) activated kinase 6) This gene encodes a member of a family of p21-stimulated serine/threonine protein kinases, which contain an amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. These kinases function in a number of cellular processes, including cytoskeleton rearrangement, apoptosis, and the mitogen-activated protein (MAP) kinase signaling pathway. The protein encoded by this gene interacts with androgen receptor (AR) and translocates to the nucleus, where it is involved in transcriptional regulation. Changes in expression of this gene have been linked to prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

LOC107984763 (HGNC:):

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=0.08176622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.2708A>G	p.Asn903Ser	missense_variant	Exon 21 of 23	ENST00000287598.11	NP_001202.5
BUB1B-PAK6	NM_001128628.3	c.-343A>G		5_prime_UTR_variant	Exon 1 of 11		NP_001122100.1
BUB1B-PAK6	NM_001128629.3	c.-260A>G		5_prime_UTR_variant	Exon 1 of 10		NP_001122101.1
LOC107984763	XR_001751506.2	n.217+21960T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.2708A>G	p.Asn903Ser	missense_variant	Exon 21 of 23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.2750A>G	p.Asn917Ser	missense_variant	Exon 21 of 23	2		ENSP00000398470.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N903S variant (also known as c.2708A>G), located in coding exon 21 of the BUB1B gene, results from an A to G substitution at nucleotide position 2708. The asparagine at codon 903 is replaced by serine, 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. -

Mosaic variegated aneuploidy syndrome 1 Uncertain:1

Feb 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with BUB1B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 903 of the BUB1B protein (p.Asn903Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.074
Sift	Benign	0.57	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.053	B;.
Vest4		0.073
MutPred		0.35		Gain of relative solvent accessibility (P = 0.0275);.;
MVP		0.74
MPC		0.16
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.039
gMVP		0.068

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: rs1595538965; hg19: chr15-40509726;