16-680670-T-G

Position:

• chr16-680670-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_005861.4(STUB1):​c.145T>G​(p.Tyr49Asp) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y49C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.12

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005861.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-680671-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1697978.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STUB1	NM_005861.4	c.145T>G	p.Tyr49Asp	missense_variant	1/7	ENST00000219548.9
STUB1	NM_001293197.2	c.-161T>G		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STUB1	ENST00000219548.9	c.145T>G	p.Tyr49Asp	missense_variant	1/7	1	NM_005861.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2023

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. This variant disrupts the Tyr49 amino acid residue in STUB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32713943, 33417001, 33624863). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt STUB1 protein function. This variant has not been reported in the literature in individuals affected with STUB1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 49 of the STUB1 protein (p.Tyr49Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.74		Loss of MoRF binding (P = 0.0536);Loss of MoRF binding (P = 0.0536);
MVP		0.83
MPC		2.8
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.91

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.

Other links and lift over

hg19: chr16-730670;