16-681811-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_005861.4(STUB1):c.543G>T(p.Gln181His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,603,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q181Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

STUB1
NM_005861.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.15

Publications

1 publications found

Variant links:

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]

STUB1 links:

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]

JMJD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 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=0.038938373).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000302 (46/152366) while in subpopulation AFR AF = 0.00108 (45/41592). AF 95% confidence interval is 0.000831. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 34. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STUB1	NM_005861.4	MANE Select	c.543G>T	p.Gln181His	missense	Exon 4 of 7	NP_005852.2	Q9UNE7-1
JMJD8	NM_001005920.4	MANE Select	c.*983C>A		3_prime_UTR	Exon 9 of 9	NP_001005920.3	Q96S16-1
STUB1	NM_001293197.2		c.327G>T	p.Gln109His	missense	Exon 4 of 7	NP_001280126.1	Q9UNE7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STUB1	ENST00000219548.9	TSL:1 MANE Select	c.543G>T	p.Gln181His	missense	Exon 4 of 7	ENSP00000219548.4	Q9UNE7-1
STUB1	ENST00000565677.5	TSL:1	c.327G>T	p.Gln109His	missense	Exon 4 of 7	ENSP00000457228.1	Q9UNE7-2
JMJD8	ENST00000609261.6	TSL:1 MANE Select	c.*983C>A		3_prime_UTR	Exon 9 of 9	ENSP00000477481.1	Q96S16-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000528

AC:

AN:

246304

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.000813

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:

0.0000165

AC:

AN:

1450844

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

719938

show subpopulations

African (AFR)

AF:

0.000660

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

39444

South Asian (SAS)

AF:

0.00

AC:

AN:

85650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51914

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104678

Other (OTH)

AF:

0.0000334

AC:

AN:

59900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41592

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000389

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000907

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.090

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

M_CAP

Benign

0.011

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.2

REVEL

Benign

0.096

Sift

Uncertain

0.026

Sift4G

Benign

0.099

Polyphen

0.60

Vest4

0.44

MutPred

0.16

Loss of stability (P = 0.257)

MVP

0.39

MPC

0.064

ClinPred

0.052

GERP RS

4.2

PromoterAI

-0.048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.29

Mutation Taster

=71/29

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over