rs146251364

Variant names:

• chr16-681512-A-C
• rs146251364
• NM_005861.4:c.433A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP2 PP5 BP4 BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:7
• Conservation: PhyloP100: 7.04
• Publications: 20 publications found

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]

JMJD8 (HGNC:14148): (jumonji domain containing 8) Involved in several processes, including positive regulation of I-kappaB kinase/NF-kappaB signaling; positive regulation of sprouting angiogenesis; and regulation of glycolytic process. Located in endoplasmic reticulum lumen and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• 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.
• 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 VariationId is 212325.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. 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	c.433A>C	p.Lys145Gln	missense_variant	Exon 3 of 7	ENST00000219548.9	NP_005852.2
JMJD8	NM_001005920.4	c.*1282T>G		downstream_gene_variant		ENST00000609261.6	NP_001005920.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9	c.433A>C	p.Lys145Gln	missense_variant	Exon 3 of 7	1	NM_005861.4	ENSP00000219548.4
JMJD8	ENST00000609261.6	c.*1282T>G		downstream_gene_variant		1	NM_001005920.4	ENSP00000477481.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152228 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.000594 AC: 148 AN: 249012 AF XY: 0.000591

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 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

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000336 AC: 15 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86198

European-Finnish (FIN) AF: 0.00152 AC: 79 AN: 52090

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5650

European-Non Finnish (NFE) AF: 0.000529 AC: 588 AN: 1111918

Other (OTH) AF: 0.000381 AC: 23 AN: 60364

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74512

African (AFR) AF: 0.000433 AC: 18 AN: 41600

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000732 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:10 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16 Pathogenic:9 Uncertain:2

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

- -

Feb 25, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

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 -

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. -

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 -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:1

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. -

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) -

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

- -

Spinocerebellar ataxia 48;C5190574:Autosomal recessive spinocerebellar ataxia 16 Uncertain:1

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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. -

Spinocerebellar ataxia 48 Uncertain:1

Jul 17, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting,PP5_Moderate,PM1 -

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;.;.
PhyloP100		7.0
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
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.74
gMVP		0.44
Mutation Taster		=51/49	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: rs146251364; hg19: chr16-731512; COSMIC: COSV50196600; COSMIC: COSV50196600;