rs146251364

Positions:

chr16-681512-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_005861.4(STUB1):c.433A>C(p.Lys145Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000538 in 1,612,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

STUB1
NM_005861.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:5

Conservation

PhyloP100: 7.04

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 16-681512-A-C is Pathogenic according to our data. Variant chr16-681512-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212325.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=2, Uncertain_significance=5}.

BP4

Computational evidence support a benign effect (MetaRNN=0.0405955). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STUB1	NM_005861.4 linkuse as main transcript	c.433A>C	p.Lys145Gln	missense_variant	3/7	ENST00000219548.9
STUB1	NM_001293197.2 linkuse as main transcript	c.217A>C	p.Lys73Gln	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STUB1	ENST00000219548.9 linkuse as main transcript	c.433A>C	p.Lys145Gln	missense_variant	3/7	1	NM_005861.4	P1	Q9UNE7-1

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000594

AC:

148

AN:

249012

Hom.:

AF XY:

0.000591

AC XY:

AN XY:

135268

show subpopulations

Gnomad AFR exome

AF:

0.000624

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.000601

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.000669

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000529

AC:

772

AN:

1460224

Hom.:

Cov.:

AF XY:

0.000559

AC XY:

406

AN XY:

726376

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00152

Gnomad4 NFE exome

AF:

0.000529

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000630

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000859

Hom.:

Bravo

AF:

0.000536

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000677

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16

Pathogenic:7Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.433A>C(p.Lys145Gln) in STUB1 gene has been reported previously in homozygous state in individuals with clinical features of autosomal recessive Spinocerebellar ataxia (Ravel JM, et al., 2021, Schuster S, et al., 2020). Experimental studies have shown that this missense change does not substantially affect STUB1 function (Kanack AJ, et al., 2018). The c.433A>C variant has 0.01% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/ Likely Pathogenic/ Uncertain Significance. The amino acid Lysine at position 145 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Lys145Gln in STUB1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 25, 2021	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 30, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 01, 2022	ACMG classification criteria: PM3 strong, PP1 moderated -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 21, 2023	This STUB1 variant (rs146251364) is rare (<0.1%) in a large population dataset (gnomAD 171/280402 total alleles; 0.06%; 1 homozygote) and has been reported in ClinVar. This missense change has been observed in individuals with clinical features of spinocerebellar ataxia, autosomal recessive 16 (SCAR16) and has been observed to segregate with disease in families. In vitro studies using transfected cells have shown that this missense change has a moderate effect on STUB1 function. However, functional analysis in cortical neurons derived from patient fibroblasts containing c.433A>C (p.Lys145Gln) and c.728C>T (p.Pro243Leu) in the compound heterozygote state demonstrated reduced STUB1/CHIP protein levels. Bioinformatic analysis predicts that this missense variant would not affect normal exon 3 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.433A>C (p.Lys145Gln) to be likely pathogenic for SCAR16. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 27, 2014

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The c.433A>C (p.K145Q) alteration is located in exon 3 (coding exon 3) of the STUB1 gene. This alteration results from a A to C substitution at nucleotide position 433, causing the lysine (K) at amino acid position 145 to be replaced by a glutamine (Q). This alteration has been reported in multiple individuals with features of STUB1-related spinocerebellar ataxia (Benkirane, 2021; Coutelier, 2017; Sun, 2019). Functional analysis demonstrated reduced CHIP protein levels in cortical neurons derived from patient fibroblasts containing c.433A>C (p.K145Q) and c.728C>T (p.P243L) in the compound heterozygote state (Schuster, 2020). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the STUB1 protein (p.Lys145Gln). This variant is present in population databases (rs146251364, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive spinocerebellar ataxia (PMID: 24719489, 28193272, 28193273, 28444220, 29915382, 32367277, 33417001, 34663476). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STUB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect STUB1 function (PMID: 28396517, 29317501). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Benign

0.94

DEOGEN2

Uncertain

0.51

.;D;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Benign

0.060

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.3

N;N;D;N

REVEL

Pathogenic

0.68

Sift

Benign

0.18

T;T;D;T

Sift4G

Benign

0.40

T;T;D;T

Polyphen

0.80

.;P;.;.

Vest4

0.82

MVP

0.41

MPC

1.1

ClinPred

0.044

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.74

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over