dbSNP rs1555475529: STUB1:p.Glu278AsnfsTer9 (chr16-682407-AG-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_ModeratePS3PM2PP5

The NM_005861.4(STUB1):c.832delG(p.Glu278AsnfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004399941: Experimental studies have shown that this premature translational stop signal affects STUB1 function (PMID:34565360).".

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

STUB1
NM_005861.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 4.15

Publications

2 publications found

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:

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]

JMJD8 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005861.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0877 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004399941: Experimental studies have shown that this premature translational stop signal affects STUB1 function (PMID: 34565360).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-682407-AG-A is Pathogenic according to our data. Variant chr16-682407-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436890.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005861.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STUB1	NM_005861.4	MANE Select	c.832delG	p.Glu278AsnfsTer9	frameshift	Exon 7 of 7	NP_005852.2	Q9UNE7-1
JMJD8	NM_001005920.4	MANE Select	c.*386delC		3_prime_UTR	Exon 9 of 9	NP_001005920.3	Q96S16-1
STUB1	NM_001293197.2		c.616delG	p.Glu206AsnfsTer9	frameshift	Exon 7 of 7	NP_001280126.1	Q9UNE7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STUB1	ENST00000219548.9	TSL:1 MANE Select	c.832delG	p.Glu278AsnfsTer9	frameshift	Exon 7 of 7	ENSP00000219548.4	Q9UNE7-1
STUB1	ENST00000565677.5	TSL:1	c.616delG	p.Glu206AsnfsTer9	frameshift	Exon 7 of 7	ENSP00000457228.1	Q9UNE7-2
JMJD8	ENST00000609261.6	TSL:1 MANE Select	c.*386delC		3_prime_UTR	Exon 9 of 9	ENSP00000477481.1	Q96S16-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461044

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Spinocerebellar ataxia 48 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over