chr16-680569-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001293197.2(STUB1):c.-262C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000667 in 1,379,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

STUB1
NM_001293197.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.77

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028696567).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000926 (14/151202) while in subpopulation AMR AF= 0.000462 (7/15164). AF 95% confidence interval is 0.000216. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
STUB1	NM_005861.4 link	c.44C>T	p.Ala15Val	missense_variant	Exon 1 of 7	ENST00000219548.9	NP_005852.2
STUB1	NM_001293197.2 link	c.-262C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7		NP_001280126.1
STUB1	NM_001293197.2 link	c.-262C>T		5_prime_UTR_variant	Exon 1 of 7		NP_001280126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STUB1	ENST00000219548.9 link	c.44C>T	p.Ala15Val	missense_variant	Exon 1 of 7	1	NM_005861.4	ENSP00000219548.4		Q9UNE7-1

Frequencies

GnomAD3 genomes

AF:

0.0000926

AC:

AN:

151202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000462

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:

0.0000591

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.0000776

AC:

AN:

90184

Hom.:

AF XY:

0.0000575

AC XY:

AN XY:

52168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000195

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.000466

GnomAD4 exome

AF:

0.0000635

AC:

AN:

1228178

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

603786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000367

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000556

Gnomad4 OTH exome

AF:

0.000310

GnomAD4 genome

AF:

0.0000926

AC:

AN:

151202

Hom.:

Cov.:

AF XY:

0.0000948

AC XY:

AN XY:

73878

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000462

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.0000629

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000261

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1879317). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 15 of the STUB1 protein (p.Ala15Val). This variant is present in population databases (rs770617507, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STUB1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

STUB1: PM2:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.34

N;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.072

Sift

Benign

0.087

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.028

B;.

Vest4

0.12

MutPred

0.12

Loss of methylation at R12 (P = 0.1114);Loss of methylation at R12 (P = 0.1114);

MVP

0.24

MPC

0.97

ClinPred

0.033

GERP RS

1.3

Varity_R

0.067

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over