rs1555475794

Variant names:

• chr16-682729-T-C
• rs1555475794
• ENST00000567120.5:n.1147A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000567120.5(JMJD8):​n.1147A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JMJD8 ENST00000567120.5 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.53
• Publications: 1 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 48

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive spinocerebellar ataxia 16

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-682729-T-C is Pathogenic according to our data. Variant chr16-682729-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522378.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STUB1	NM_005861.4	c.*240T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000219548.9	NP_005852.2
JMJD8	NM_001005920.4	c.*65A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000609261.6	NP_001005920.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9	c.*240T>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_005861.4	ENSP00000219548.4
JMJD8	ENST00000609261.6	c.*65A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001005920.4	ENSP00000477481.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16 Pathogenic:1

Feb 08, 2018

University of Uludag Hospital, Genetic Diseases Diagnostic Center, University of Uludag

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Drastically low levels of STUB1 protein in patients. Not present in any database. Absent from controls and located in a highly conserved region of the gene. Cosegregation with disease in multiple affected family members (3 affected patients) in the STUB1 gene definitively known to cause SCAR16. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.76
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs1555475794; hg19: chr16-732729;