rs61756347

chr9-32542965-T-Cchr9-32542965-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005802.5(TOPORS):c.1560A>G(p.Gln520=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,210 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: TOPORS NM_005802.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.52

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 9-32542965-T-C is Benign according to our data. Variant chr9-32542965-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 167741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-32542965-T-C is described in Lovd as [Benign]. Variant chr9-32542965-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00207 (315/152342) while in subpopulation AFR AF= 0.00236 (98/41568). AF 95% confidence interval is 0.00198. There are 1 homozygotes in gnomad4. There are 164 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOPORS	NM_005802.5	c.1560A>G	p.Gln520=	synonymous_variant	3/3	ENST00000360538.7
TOPORS	NM_001195622.2	c.1365A>G	p.Gln455=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOPORS	ENST00000360538.7	c.1560A>G	p.Gln520=	synonymous_variant	3/3	1	NM_005802.5	P3
TOPORS	ENST00000379858.1	c.1365A>G	p.Gln455=	synonymous_variant	2/2	1		A1

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00179 AC: 449 AN: 251416 Hom.: 1 AF XY: 0.00161 AC XY: 219 AN XY: 135880

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00979

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00139 AC: 2029 AN: 1461868 Hom.: 4 Cov.: 35 AF XY: 0.00136 AC XY: 990 AN XY: 727230

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.00121

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74502

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.8
Dann	Benign	0.54

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

Other links and lift over

dbSNP: rs61756347; hg19: chr9-32542963;