NM_005861.4:c.721C>G

Variant names:

• chr16-682216-C-G
• rs760424025
• NM_005861.4:c.721C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_005861.4(STUB1):​c.721C>G​(p.Arg241Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,544 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R241P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.21
• Publications: 8 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: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr16-682216-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1027452.Status of the report is criteria_provided_single_submitter, 1 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, 0.851
• PP5: Variant 16-682216-C-G is Pathogenic according to our data. Variant chr16-682216-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 436889.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STUB1	NM_005861.4	MANE Select	c.721C>G	p.Arg241Gly	missense	Exon 6 of 7	NP_005852.2
	JMJD8	NM_001005920.4	MANE Select	c.*578G>C		3_prime_UTR	Exon 9 of 9	NP_001005920.3
	STUB1	NM_001293197.2		c.505C>G	p.Arg169Gly	missense	Exon 6 of 7	NP_001280126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STUB1	ENST00000219548.9	TSL:1 MANE Select	c.721C>G	p.Arg241Gly	missense	Exon 6 of 7	ENSP00000219548.4
	STUB1	ENST00000565677.5	TSL:1	c.505C>G	p.Arg169Gly	missense	Exon 6 of 7	ENSP00000457228.1
	JMJD8	ENST00000609261.6	TSL:1 MANE Select	c.*578G>C		3_prime_UTR	Exon 9 of 9	ENSP00000477481.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250190 AF XY: 0.00000738

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460544 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726508

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52356

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive spinocerebellar ataxia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		1.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.37
Sift	Benign	0.034	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.59		Loss of loop (P = 0.1242)
MVP		0.58
MPC		0.34
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.82
gMVP		0.79
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760424025; hg19: chr16-732216;