rs146251364

chr16-681512-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

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:7 U:4
• Conservation: PhyloP100: 7.04

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]

ACMG classification

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: {Uncertain_significance=4, Pathogenic=3, Likely_pathogenic=2}.
• 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	c.433A>C	p.Lys145Gln	missense_variant	3/7	ENST00000219548.9
STUB1	NM_001293197.2	c.217A>C	p.Lys73Gln	missense_variant	3/7

Ensembl

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

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

GnomAD3 exomes AF: 0.000594 AC: 148 AN: 249012 Hom.: 0 AF XY: 0.000591 AC XY: 80 AN XY: 135268

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

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

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:7 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16 Pathogenic:7 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
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. -
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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 30, 2022	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -

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

Invitae

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	T
BayesDel_noAF	Benign	-0.38
Cadd	Pathogenic	28
Dann	Benign	0.94
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.041	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N;D;N
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

Other links and lift over

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