chr9-32541397-TCA-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_ModeratePP5BS1_SupportingBS2

The NM_005802.5(TOPORS):c.3126_3127delTG(p.Cys1042fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TOPORS
NM_005802.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 1.96

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 -2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00382 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PP5

Variant 9-32541397-TCA-T is Pathogenic according to our data. Variant chr9-32541397-TCA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 940703.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000263 (4/152222) while in subpopulation AMR AF= 0.000131 (2/15288). AF 95% confidence interval is 0.0000226. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 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 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPORS	NM_005802.5 link	c.3126_3127delTG	p.Cys1042fs	frameshift_variant	Exon 3 of 3	ENST00000360538.7	NP_005793.2	Q9NS56-1
TOPORS	NM_001195622.2 link	c.2931_2932delTG	p.Cys977fs	frameshift_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.3126_3127delTG	p.Cys1042fs	frameshift_variant	Exon 3 of 3	1	NM_005802.5	ENSP00000353735.2	Q9NS56-1
TOPORS	ENST00000379858.1 link	c.2931_2932delTG	p.Cys977fs	frameshift_variant	Exon 2 of 2	1		ENSP00000369187.1	Q9NS56-2
ENSG00000288684	ENST00000681750.1 link	c.-45+9375_-45+9376delTG		intron_variant	Intron 3 of 19			ENSP00000506413.1	A0A7P0TB70
ENSG00000288684	ENST00000680198.1 link	c.198+9375_198+9376delTG		intron_variant	Intron 2 of 18			ENSP00000505143.1	A0A7P0T8K8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251336

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461832

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jul 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys1042*) in the TOPORS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the TOPORS protein. This variant is present in population databases (rs776001696, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of retinitis pigmentosa (Invitae). ClinVar contains an entry for this variant (Variation ID: 940703). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Retinitis pigmentosa 31

Uncertain:1

3billion, Medical Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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