NM_001211.6:c.-42A>G

Variant names:

• chr15-40161179-A-G
• rs183777343
• NM_001211.6:c.-42A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001211.6(BUB1B):​c.-42A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,609,880 control chromosomes in the GnomAD database, including 168 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 0.010 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (154 hom.)
• Consequence: BUB1B NM_001211.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.156
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1552/152254) while in subpopulation NFE AF = 0.0142 (968/68012). AF 95% confidence interval is 0.0135. There are 14 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BUB1B	NM_001211.6	c.-42A>G		5_prime_UTR_variant	Exon 1 of 23	ENST00000287598.11	NP_001202.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BUB1B	ENST00000287598.11	c.-42A>G		5_prime_UTR_variant	Exon 1 of 23	1	NM_001211.6	ENSP00000287598.7
BUB1B	ENST00000412359.7	c.-42A>G		5_prime_UTR_variant	Exon 1 of 23	2		ENSP00000398470.3

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1552 AN: 152136 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00999 AC: 2420 AN: 242150 AF XY: 0.00965

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00355

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0352

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.00829

GnomAD4 exome AF: 0.0124 AC: 18140 AN: 1457626 Hom.: 154 Cov.: 31 AF XY: 0.0122 AC XY: 8820 AN XY: 724724

African (AFR) AF: 0.00171 AC: 57 AN: 33386

American (AMR) AF: 0.00384 AC: 170 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.00434 AC: 113 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.000680 AC: 58 AN: 85340

European-Finnish (FIN) AF: 0.0352 AC: 1871 AN: 53164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0137 AC: 15210 AN: 1110014

Other (OTH) AF: 0.0110 AC: 661 AN: 60172

GnomAD4 genome AF: 0.0102 AC: 1552 AN: 152254 Hom.: 14 Cov.: 32 AF XY: 0.0105 AC XY: 784 AN XY: 74442

African (AFR) AF: 0.00209 AC: 87 AN: 41538

American (AMR) AF: 0.00627 AC: 96 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0348 AC: 369 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 968 AN: 68012

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.0125 Hom.: 4

Bravo AF: 0.00770

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2019

GeneDx

Significance: Likely 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	-0.82
CADD	Benign	8.6
DANN	Benign	0.66
PhyloP100		0.16
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs183777343; hg19: chr15-40453380; COSMIC: COSV55014982;