rs146251364

Variant names:

• chr16-681512-A-C
• rs146251364
• NM_005861.4:c.433A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP2 PP5 BP4 BS1_Supporting

The NM_005861.4(STUB1):​c.433A>C​(p.Lys145Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000538 in 1,612,570 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:7
• Conservation: PhyloP100: 7.04
• Publications: 20 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• 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.
• PP5: Variant 16-681512-A-C is Pathogenic according to our data. Variant chr16-681512-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212325.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0405955). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00063 (96/152346) while in subpopulation AMR AF = 0.000915 (14/15306). AF 95% confidence interval is 0.000552. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STUB1	NM_005861.4	MANE Select	c.433A>C	p.Lys145Gln	missense	Exon 3 of 7	NP_005852.2	Q9UNE7-1
	STUB1	NM_001293197.2		c.217A>C	p.Lys73Gln	missense	Exon 3 of 7	NP_001280126.1	Q9UNE7-2
	JMJD8	NM_001005920.4	MANE Select	c.*1282T>G		downstream_gene	N/A	NP_001005920.3	Q96S16-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STUB1	ENST00000219548.9	TSL:1 MANE Select	c.433A>C	p.Lys145Gln	missense	Exon 3 of 7	ENSP00000219548.4	Q9UNE7-1
	STUB1	ENST00000565677.5	TSL:1	c.217A>C	p.Lys73Gln	missense	Exon 3 of 7	ENSP00000457228.1	Q9UNE7-2
	STUB1	ENST00000965393.1		c.433A>C	p.Lys145Gln	missense	Exon 3 of 7	ENSP00000635452.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000594 AC: 148 AN: 249012 AF XY: 0.000591

Gnomad AFR exome AF: 0.000624

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.000601

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000529 AC: 772 AN: 1460224 Hom.: 1 Cov.: 31 AF XY: 0.000559 AC XY: 406 AN XY: 726376

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000336 AC: 15 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86198

European-Finnish (FIN) AF: 0.00152 AC: 79 AN: 52090

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5650

European-Non Finnish (NFE) AF: 0.000529 AC: 588 AN: 1111918

Other (OTH) AF: 0.000381 AC: 23 AN: 60364

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74512

African (AFR) AF: 0.000433 AC: 18 AN: 41600

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000677 AC: 82

EpiCase AF: 0.000709

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	2	-	Autosomal recessive spinocerebellar ataxia 16 (11)
1	1	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Spinocerebellar ataxia 48 (1)
-	1	-	Spinocerebellar ataxia 48;C5190574:Autosomal recessive spinocerebellar ataxia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	28
DANN	Benign	0.94
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.68
Sift	Benign	0.18	T
Sift4G	Benign	0.40	T
Polyphen		0.80	P
Vest4		0.82
MVP		0.41
MPC		1.1
ClinPred		0.044	T
GERP RS		4.6
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.74
gMVP		0.44
Mutation Taster		=51/49	polymorphism

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: rs146251364; hg19: chr16-731512; COSMIC: COSV50196600; COSMIC: COSV50196600;