16-681845-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005861.4(STUB1):​c.577G>C​(p.Val193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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 Likely benign.

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

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041888446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STUB1	NM_005861.4	c.577G>C	p.Val193Leu	missense_variant	Exon 4 of 7	ENST00000219548.9	NP_005852.2
JMJD8	NM_001005920.4	c.*949C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000609261.6	NP_001005920.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9	c.577G>C	p.Val193Leu	missense_variant	Exon 4 of 7	1	NM_005861.4	ENSP00000219548.4
JMJD8	ENST00000609261	c.*949C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001005920.4	ENSP00000477481.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.047
DANN	Benign	0.65
DEOGEN2	Benign	0.28	.;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	.;T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	.;N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.29	N;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.91	T;T;T;T
Sift4G	Benign	0.80	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.22
MutPred		0.14		.;Gain of phosphorylation at S191 (P = 0.2966);.;.;
MVP		0.15
MPC		0.055
ClinPred		0.021	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.33

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: rs200514887; hg19: chr16-731845;