chr16-681512-A-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting

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:10U: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 Likely_benign. Variant got -1 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: {Uncertain_significance=5, Pathogenic=4, Likely_pathogenic=4}.

BP4

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

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00063 (96/152346) while in subpopulation AMR AF= 0.000915 (14/15306). AF 95% confidence interval is 0.000552. There are 1 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STUB1	NM_005861.4 link	c.433A>C	p.Lys145Gln	missense_variant	Exon 3 of 7	ENST00000219548.9	NP_005852.2
STUB1	NM_001293197.2 link	c.217A>C	p.Lys73Gln	missense_variant	Exon 3 of 7		NP_001280126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9 link	c.433A>C	p.Lys145Gln	missense_variant	Exon 3 of 7	1	NM_005861.4	ENSP00000219548.4		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:10Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16

Pathogenic:9Uncertain:2

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are suggested mechanisms of disease in this gene and are associated with spinocerebellar ataxia 48 (MIM#618093) and spinocerebellar ataxia 16 (MIM#615768), respectively (PMID: 34565360). (I) 0108 - This gene is associated with both recessive and dominant disease. Monoallelic variants have been reported to result in SCA48, whereas biallelic variants have been associated with SCA16 (PMID: 34565360). However, it remains unclear why p.(Arg241Trp) and p.(Cys232Gly) have been associated with both phenotypes (PMID: 33417001). (I) 0115 - Variants in this gene are known to have variable expressivity. There is interfamilial and intrafamilial variability of both severity and features (PMID: 33417001). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (169 heterozygotes, 1 homozygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated CHIP domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous in at least five unrelated individuals with ataxia (VCGS, PMIDs: 28193273, 28444220, 29915382, 32367277, 34234304, 34663476). It has also been reported as VUS in ClinVar but without further curation information provided. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STUB1 c.433A>C (p.Lys145Gln) results in a conservative amino acid change located in the CHIP N-terminal tetratricopeptide repeat domain (IPR041312) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 1460224 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in STUB1 causing Autosomal Recessive Spinocerebellar Ataxia 16, allowing no conclusion about variant significance. c.433A>C has been reported in the literature in multiple compound heterozygous individuals affected with Autosomal Recessive Spinocerebellar Ataxia 16 (e.g. Depondt_2014, Hayer_2017, Coutelier_2017, Sun_2019, Chiu_2020, Ravel_2021, Cheng_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pakdaman_2017, Kanack_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 34663476, 32367277, 28444220, 24719489, 28193273, 29317501, 28396517, 33417001, 29915382). ClinVar contains an entry for this variant (Variation ID: 212325). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 30, 2022

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM3 strong, PP1 moderated -

Feb 25, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 21, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Uncertain:1

Jun 08, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate only a mild functional effect (PMID: 29317501, 28396517); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25363768, 24719489, 28396517, 34426522, 34011629, 34445196, 34234304, 28193273, 33417001, 29317501, 34758253, 34663476, 32367277, 29915382, 33097556, 36853170, 28444220) -

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Uncertain:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;.;.

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

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