rs762457246

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBS1_SupportingBS2

The NM_005802.5(TOPORS):c.2666A>G(p.His889Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,032 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H889P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TOPORS
NM_005802.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.38

Variant links:

Genes affected

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:

ENSG00000288684 (HGNC:):

ENSG00000288684 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-32541859-T-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.19060707).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000287 (42/1461818) while in subpopulation SAS AF= 0.000278 (24/86252). AF 95% confidence interval is 0.000192. There are 0 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPORS	NM_005802.5 link	c.2666A>G	p.His889Arg	missense_variant	Exon 3 of 3	ENST00000360538.7	NP_005793.2	Q9NS56-1
TOPORS	NM_001195622.2 link	c.2471A>G	p.His824Arg	missense_variant	Exon 2 of 2		NP_001182551.1	Q9NS56-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TOPORS	ENST00000360538.7 link	c.2666A>G	p.His889Arg	missense_variant	Exon 3 of 3	1	NM_005802.5	ENSP00000353735.2	Q9NS56-1
TOPORS	ENST00000379858.1 link	c.2471A>G	p.His824Arg	missense_variant	Exon 2 of 2	1		ENSP00000369187.1	Q9NS56-2
ENSG00000288684	ENST00000681750.1 link	c.-45+8915A>G		intron_variant	Intron 3 of 19			ENSP00000506413.1	A0A7P0TB70
ENSG00000288684	ENST00000680198.1 link	c.198+8915A>G		intron_variant	Intron 2 of 18			ENSP00000505143.1	A0A7P0T8K8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251198

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 31

Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Hypermetropia;C0730292:Macular dystrophy;C1839025:Decreased light- and dark-adapted electroretinogram amplitude;C1862475:Abnormality of retinal pigmentation;C4024790:Adult-onset night blindness;C4025846:Abnormality of vision;C4551715:Pigmentary retinopathy

Uncertain:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 889 of the TOPORS protein (p.His889Arg). This variant is present in population databases (rs762457246, gnomAD 0.03%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 26720483). ClinVar contains an entry for this variant (Variation ID: 523487). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0050

D;D

Sift4G

Benign

0.21

T;T

Polyphen

0.99

D;.

Vest4

0.42

MutPred

0.082

Gain of methylation at K894 (P = 0.1209);.;

MVP

0.46

MPC

0.38

ClinPred

0.26

GERP RS

5.0

Varity_R

0.15

gMVP

0.24

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