Variant 16-680528-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_005861.4(STUB1):c.3G>T(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STUB1
NM_005861.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.84

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:

STUB1 (HGNC:):

STUB1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_005861.4 (STUB1) was described as [Likely_pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-680528-G-T is Pathogenic according to our data. Variant chr16-680528-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3377516.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STUB1	NM_005861.4 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/7	ENST00000219548.9	NP_005852.2
STUB1	NM_001293197.2 linkuse as main transcript	c.-303G>T		5_prime_UTR_variant	1/7		NP_001280126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9 linkuse as main transcript	c.3G>T	p.Met1?	start_lost	1/7	1	NM_005861.4	ENSP00000219548.4		Q9UNE7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1124196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

541488

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spinocerebellar ataxia 48

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely 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 (SCA48; 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) 0207 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG) but an alternative initiation codon is known to exist. This downstream start codon (p.Met73) is utilised as the start codon of NM_001293197.2 (UCSC). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0704 - Another start-loss variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This variant (c.3G>A) has been reported as de novo in an individual with symptoms including cerebellar ataxia and atrophy, myoclonus and mild spasticity (PMID: 33564152, PMID: 33811518). Another comparable variant (c.1A>G) has been reported as a VUS (LOVD). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a heterozygous individual with cognitive decline and cerebellar ataxia, who was also heterozygous for a 44-glutamine repeat in the TBP gene (PMID: 34906452). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.093

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.67

D;D

MetaSVM

Benign

-1.1

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0030

B;.

Vest4

0.76

MutPred

0.50

Gain of methylation at K2 (P = 0.0333);Gain of methylation at K2 (P = 0.0333);

MVP

0.59

ClinPred

0.99

GERP RS

3.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.84

gMVP

0.36

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over