11-116758326-C-T

Variant names:

• chr11-116758326-C-T
• rs143244324
• NM_032725.4:c.1442G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032725.4(BUD13):​c.1442G>A​(p.Arg481Lys) 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 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R481M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BUD13 NM_032725.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666
• Publications: 0 publications found

Genes affected

BUD13 (HGNC:28199): (BUD13 homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleoplasm. Part of U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

BUD13 Gene-Disease associations (from GenCC):

• progeroid syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000308823 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08577266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032725.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUD13	NM_032725.4	MANE Select	c.1442G>A	p.Arg481Lys	missense	Exon 7 of 10	NP_116114.1	Q9BRD0-1
	BUD13	NM_001159736.2		c.1040G>A	p.Arg347Lys	missense	Exon 7 of 10	NP_001153208.1	Q9BRD0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BUD13	ENST00000260210.5	TSL:1 MANE Select	c.1442G>A	p.Arg481Lys	missense	Exon 7 of 10	ENSP00000260210.3	Q9BRD0-1
	BUD13	ENST00000375445.7	TSL:1	c.1040G>A	p.Arg347Lys	missense	Exon 7 of 10	ENSP00000364594.3	Q9BRD0-2
	BUD13	ENST00000911264.1		c.1439G>A	p.Arg480Lys	missense	Exon 7 of 10	ENSP00000581323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
PhyloP100		0.67
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.078
Sift	Benign	0.47	T
Sift4G	Benign	0.48	T
Polyphen		0.21	B
Vest4		0.11
MutPred		0.53		Gain of ubiquitination at R481 (P = 0.0162)
MVP		0.47
MPC		0.11
ClinPred		0.72	D
GERP RS		4.7
Varity_R		0.16
gMVP		0.056
Mutation Taster		=92/8	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: rs143244324; hg19: chr11-116629042;