Genetic Variant STUB1:p.Arg35Pro (chr16-680629-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_005861.4(STUB1):c.104G>C(p.Arg35Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STUB1
NM_005861.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

Publications

0 publications found

Variant links:

Genes affected

STUB1 (HGNC:11427): (STIP1 homology and U-box containing protein 1) This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2. [provided by RefSeq, Jun 2014]

STUB1 Gene-Disease associations (from GenCC):

spinocerebellar ataxia 48
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal recessive spinocerebellar ataxia 16
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

STUB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.1638 (below the threshold of 3.09). Trascript score misZ: -0.9945 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive spinocerebellar ataxia 16, spinocerebellar ataxia 48.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005861.4. 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
	STUB1	NM_005861.4	MANE Select	c.104G>C	p.Arg35Pro	missense	Exon 1 of 7	NP_005852.2	Q9UNE7-1
	STUB1	NM_001293197.2		c.-202G>C		5_prime_UTR	Exon 1 of 7	NP_001280126.1	Q9UNE7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STUB1	ENST00000219548.9	TSL:1 MANE Select	c.104G>C	p.Arg35Pro	missense	Exon 1 of 7	ENSP00000219548.4	Q9UNE7-1
STUB1	ENST00000565677.5	TSL:1	c.-202G>C		5_prime_UTR	Exon 1 of 7	ENSP00000457228.1	Q9UNE7-2
STUB1	ENST00000965393.1		c.104G>C	p.Arg35Pro	missense	Exon 1 of 7	ENSP00000635452.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1232156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

605150

African (AFR)

AF:

0.00

AC:

AN:

25162

American (AMR)

AF:

0.00

AC:

AN:

21080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19548

East Asian (EAS)

AF:

0.00

AC:

AN:

28110

South Asian (SAS)

AF:

0.00

AC:

AN:

53942

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4898

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

990166

Other (OTH)

AF:

0.00

AC:

AN:

48290

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

PhyloP100

2.5

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.45

Sift

Uncertain

0.018

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.68

MutPred

0.47

Loss of MoRF binding (P = 0.0059)

MVP

0.80

MPC

2.4

ClinPred

0.99

GERP RS

3.5

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.81

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over