chr9-32550898-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000681750.1(ENSG00000288684):c.-169C>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 0.0000986 in 1,612,856 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 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ENSG00000288684
ENST00000681750.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.417

Publications

11 publications found

Variant links:

Genes affected

ENSG00000288684 (HGNC:):

ENSG00000288684 links:

TOPORS (HGNC:21653): (TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase) This gene encodes a nuclear protein which is serine and arginine rich, and contains a RING-type zinc finger domain. It is highly expressed in the testis, and functions as an ubiquitin-protein E3 ligase. Mutations in this gene are associated with retinitis pigmentosa type 31. Alternatively spliced transcript variants, encoding different isoforms, have been observed for this locus. [provided by RefSeq, Sep 2010]

TOPORS links:

SMIM27 (HGNC:31420): (small integral membrane protein 27) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM27 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03411278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPORS	NM_005802.5 link	c.74C>T	p.Ser25Leu	missense_variant	Exon 2 of 3	ENST00000360538.7	NP_005793.2	Q9NS56-1
TOPORS	NM_001195622.2 link	c.3+1536C>T		intron_variant	Intron 1 of 1		NP_001182551.1	Q9NS56-2
SMIM27	NM_001349118.1 link	c.-997G>A		upstream_gene_variant			NP_001336047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000288684	ENST00000681750.1 link	c.-169C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 20			ENSP00000506413.1	A0A7P0TB70
TOPORS	ENST00000360538.7 link	c.74C>T	p.Ser25Leu	missense_variant	Exon 2 of 3	1	NM_005802.5	ENSP00000353735.2	Q9NS56-1
ENSG00000288684	ENST00000681750.1 link	c.-169C>T		5_prime_UTR_variant	Exon 3 of 20			ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000107

AC:

AN:

242688

AF XY:

0.000158

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000873

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

150

AN:

1460640

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

726682

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.0000671

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000383

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52538

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000935

AC:

104

AN:

1111792

Other (OTH)

AF:

0.000116

AC:

AN:

60338

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

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:

0.0000591

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000826

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 25 of the TOPORS protein (p.Ser25Leu). This variant is present in population databases (rs61758066, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TOPORS-related conditions. ClinVar contains an entry for this variant (Variation ID: 450158). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Jul 06, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The S25L variant in the TOPORS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S25L variant is observed in 5/16314 (0.03%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). The S25L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S25L as a variant of uncertain significance. -

Retinitis pigmentosa

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0080

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.72

M_CAP

Benign

0.013

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.42

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.070

REVEL

Benign

0.033

Sift

Benign

0.19

Sift4G

Benign

0.20

Polyphen

0.012

Vest4

0.13

MutPred

0.24

Loss of phosphorylation at S25 (P = 0.0017);

MVP

0.12

MPC

0.28

ClinPred

0.089

GERP RS

3.4

PromoterAI

0.0014

Neutral

(source)

Varity_R

0.066

gMVP

0.54

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over