16-681845-G-T

Variant names:

• chr16-681845-G-T
• rs200514887
• NM_005861.4:c.577G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_005861.4(STUB1):​c.577G>T​(p.Val193Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V193I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56
• 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]

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: Likely_benign. The variant received -3 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.048766315).

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.577G>T	p.Val193Phe	missense	Exon 4 of 7	NP_005852.2	Q9UNE7-1
	JMJD8	NM_001005920.4	MANE Select	c.*949C>A		3_prime_UTR	Exon 9 of 9	NP_001005920.3	Q96S16-1
	STUB1	NM_001293197.2		c.361G>T	p.Val121Phe	missense	Exon 4 of 7	NP_001280126.1	Q9UNE7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STUB1	ENST00000219548.9	TSL:1 MANE Select	c.577G>T	p.Val193Phe	missense	Exon 4 of 7	ENSP00000219548.4	Q9UNE7-1
	STUB1	ENST00000565677.5	TSL:1	c.361G>T	p.Val121Phe	missense	Exon 4 of 7	ENSP00000457228.1	Q9UNE7-2
	JMJD8	ENST00000609261.6	TSL:1 MANE Select	c.*949C>A		3_prime_UTR	Exon 9 of 9	ENSP00000477481.1	Q96S16-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000802 AC: 2 AN: 249384 AF XY: 0.00000740

Gnomad AFR exome AF: 0.0000622

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459428 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 725774

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111170

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.35
DANN	Benign	0.71
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N
PhyloP100		-1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Benign	0.71	T
Sift4G	Benign	0.78	T
Polyphen		0.0020	B
Vest4		0.31
MutPred		0.14		Loss of phosphorylation at S191 (P = 0.3002)
MVP		0.081
MPC		0.071
ClinPred		0.012	T
GERP RS		-4.5
PromoterAI		0.20	Neutral
Varity_R		0.078
gMVP		0.51
Mutation Taster		=85/15	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: rs200514887; hg19: chr16-731845;