rs146251364

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

2
6
11

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]

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
STUB1NM_005861.4 linkc.433A>C p.Lys145Gln missense_variant Exon 3 of 7 ENST00000219548.9 NP_005852.2
STUB1NM_001293197.2 linkc.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
STUB1ENST00000219548.9 linkc.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:
96
AN:
152228
Hom.:
1
Cov.:
33
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.:
0
AF XY:
0.000591
AC XY:
80
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.:
1
Cov.:
31
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:
96
AN:
152346
Hom.:
1
Cov.:
33
AF XY:
0.000792
AC XY:
59
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.:
0
Bravo
AF:
0.000536
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.000582
AC:
5
ExAC
AF:
0.000677
AC:
82
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
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenAug 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based 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 -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinSep 01, 2022ACMG classification criteria: PM3 strong, PP1 moderated -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 13, 2025Variant 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. -
Likely pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submitterresearchMolecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella MarisJan 04, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityMar 21, 2023This 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 25, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMay 20, 2023The 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, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJun 08, 2024Published 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) -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 19, 2024This 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
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 27, 2014- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 01, 2023The 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
T
BayesDel_noAF
Benign
-0.38
CADD
Pathogenic
28
DANN
Benign
0.94
DEOGEN2
Uncertain
0.51
.;D;.;.
Eigen
Uncertain
0.23
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.96
.;D;D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.041
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.5
.;M;.;.
PrimateAI
Pathogenic
0.87
D
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
T
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.

Other links and lift over

dbSNP: rs146251364; hg19: chr16-731512; COSMIC: COSV50196600; COSMIC: COSV50196600; API