rs587777346

Variant names:

• chr16-681227-G-A
• rs587777346
• NM_005861.4:c.235G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_005861.4(STUB1):​c.235G>A​(p.Ala79Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.50
• Publications: 5 publications found

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 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-681228-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 127150.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 18 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.1638 (below the threshold of 3.09). Trascript score misZ: -0.9945 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive spinocerebellar ataxia 16, spinocerebellar ataxia 48.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 16-681227-G-A is Pathogenic according to our data. Variant chr16-681227-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 127149.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STUB1	NM_005861.4	c.235G>A	p.Ala79Thr	missense_variant	Exon 2 of 7	ENST00000219548.9	NP_005852.2
STUB1	NM_001293197.2	c.19G>A	p.Ala7Thr	missense_variant	Exon 2 of 7		NP_001280126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9	c.235G>A	p.Ala79Thr	missense_variant	Exon 2 of 7	1	NM_005861.4	ENSP00000219548.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245920 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459164 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725764

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111378

Other (OTH) AF: 0.0000166 AC: 1 AN: 60292

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive spinocerebellar ataxia 16 Pathogenic:1

Apr 17, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.9	.;M;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Pathogenic	0.88
Sift	Benign	0.072	T;T;D;T
Sift4G	Uncertain	0.041	D;T;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.75
MutPred		0.85		.;Gain of loop (P = 0.1069);.;.;
MVP		0.85
MPC		1.4
ClinPred		0.98	D
GERP RS		4.3
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.49
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777346; hg19: chr16-731227;