rs34700927

Positions:

• chr15-40220700-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001211.6(BUB1B):​c.3094A>C​(p.Asn1032His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,190 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: BUB1B NM_001211.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 0.695

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03814283).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000722 (110/152314) while in subpopulation NFE AF= 0.00132 (90/68022). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 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
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.3094A>C	p.Asn1032His	missense_variant	23/23	ENST00000287598.11	NP_001202.5
BUB1B-PAK6	NM_001128628.3	c.-201+3033A>C		intron_variant			NP_001122100.1
BUB1B-PAK6	NM_001128629.3	c.-118+3033A>C		intron_variant			NP_001122101.1
LOC107984763	XR_001751506.2	n.217+18785T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.3094A>C	p.Asn1032His	missense_variant	23/23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.3136A>C	p.Asn1046His	missense_variant	23/23	2		ENSP00000398470.3
BUB1B-PAK6	ENST00000559435.1	n.199A>C		non_coding_transcript_exon_variant	2/6	5		ENSP00000457109.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000708 AC: 178 AN: 251490 Hom.: 1 AF XY: 0.000750 AC XY: 102 AN XY: 135918

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00132

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00116 AC: 1696 AN: 1461876 Hom.: 3 Cov.: 31 AF XY: 0.00110 AC XY: 798 AN XY: 727236

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74482

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000848 AC: 103

EpiCase AF: 0.00131

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with pancreatic cancer (Shindo 2017); This variant is associated with the following publications: (PMID: 28767289) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BUB1B p.Asn1032His variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs34700927) as "With Uncertain significance allele" as well as in Clinvar as uncertain significance by one submitter, Invitae. The condition associated with this variant is Mosaic variegated aneuploidy syndrome. In the LOVD 3.0 database, the variant is classified as likely benign and probably does not affect protein function according to three submitters. The variant was identified in control databases in 201 of 282894 chromosomes (1 homozygous) at a frequency of 0.000711 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 172 of 129200 chromosomes (freq: 0.001331), Other in 8 of 7226 chromosomes (freq: 0.001107), Latino in 10 of 35440 chromosomes (freq: 0.000282), European (Finnish) in 5 of 25122 chromosomes (freq: 0.000199), Ashkenazi Jewish in 2 of 10370 chromosomes (freq: 0.000193), African in 4 of 24970 chromosomes (freq: 0.00016); it was not observed in the East Asian, South Asian, populations. The variant was also identified in the following databases: the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium (August 8th 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Asn1032 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, and MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. 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. -

Mosaic variegated aneuploidy syndrome 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 22, 2023	The BUB1B c.3094A>C (p.Asn1032His) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 including 1 homozygote (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with mosaic variegated aneuploidy syndrome. In summary, the evidence currently available is insufficient to determine the role of this variant in mosaic variegated aneuploidy syndrome. It has therefore been classified as of uncertain significance. -

BUB1B-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2024

The BUB1B c.3094A>C variant is predicted to result in the amino acid substitution p.Asn1032His. To our knowledge, this variant has not been reported in the literature in an individual with mosaic variegated aneuploidy syndrome (MVA). This variant has been reported in six individuals in a large pancreatic cancer cohort (Shindo et al. 2017. PubMed ID: 28767289), but it is unclear at this time whether heterozygous germline BUB1B variants are associated with an increased risk of pancreatic cancer. This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygote, and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/403757/). Although we suspect that this variant may be benign, the clinical significance of this variant is uncertain at this time due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.047
Sift	Benign	0.14	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.85	P;.
Vest4		0.18
MVP		0.78
MPC		0.37
ClinPred		0.038	T
GERP RS		3.5
Varity_R		0.054
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs34700927; hg19: chr15-40512901; COSMIC: COSV55010127; COSMIC: COSV55010127;