16-681803-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005861.4(STUB1):c.535G>A(p.Glu179Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000484 in 1,447,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: STUB1 NM_005861.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.30

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13400543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STUB1	NM_005861.4	c.535G>A	p.Glu179Lys	missense_variant	4/7	ENST00000219548.9
JMJD8	NM_001005920.4	c.*991C>T		3_prime_UTR_variant	9/9	ENST00000609261.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STUB1	ENST00000219548.9	c.535G>A	p.Glu179Lys	missense_variant	4/7	1	NM_005861.4	P1
JMJD8	ENST00000609261.6	c.*991C>T		3_prime_UTR_variant	9/9	1	NM_001005920.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 244806 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS 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: 0.00000484 AC: 7 AN: 1447654 Hom.: 0 Cov.: 33 AF XY: 0.00000557 AC XY: 4 AN XY: 717862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000508

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 03, 2024

Variant summary: STUB1 c.535G>A (p.Glu179Lys) results in a conservative amino acid change located in the CHIP, N-terminal tetratricopeptide repeat domain (IPR041312) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244806 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.535G>A in individuals affected with Autosomal Recessive Spinocerebellar Ataxia 16 and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.46
Cadd	Uncertain	23
Dann	Benign	0.92
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.65	N;N;N;N
Sift	Benign	0.42	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0040	.;B;.;.
Vest4		0.55
MutPred		0.38		.;Gain of ubiquitination at E179 (P = 0.0031);.;.;
MVP		0.29
MPC		0.061
ClinPred		0.27	T
GERP RS		4.2
Varity_R		0.15
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs764534080; hg19: chr16-731803;