rs587777344

Positions:

• chr16-681446-C-G
• chr16-681446-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000219548.9(STUB1):​c.367C>G​(p.Leu123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: STUB1 ENST00000219548.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 1.54

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant 16-681446-C-G is Pathogenic according to our data. Variant chr16-681446-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127147.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STUB1	NM_005861.4	c.367C>G	p.Leu123Val	missense_variant	3/7	ENST00000219548.9	NP_005852.2
STUB1	NM_001293197.2	c.151C>G	p.Leu51Val	missense_variant	3/7		NP_001280126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9	c.367C>G	p.Leu123Val	missense_variant	3/7	1	NM_005861.4	ENSP00000219548	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16 Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 17, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.1	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.90
MutPred		0.49		.;Gain of ubiquitination at K125 (P = 0.0898);.;.;
MVP		0.69
MPC		2.1
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.87
gMVP		0.49

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: rs587777344; hg19: chr16-731446;