9-32541247-CAA-CAAA

Variant names:

• chr9-32541247-C-CA
• rs140010425
• NM_005802.5:c.*139dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005802.5(TOPORS):​c.*139dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 768,070 control chromosomes in the GnomAD database, including 3,004 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1232 hom., cov: 29)
  • Exomes 𝑓: 0.14 (1772 hom.)
• Consequence: TOPORS NM_005802.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 31

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• TOPORS-related retinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000288684 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005802.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPORS	NM_005802.5	MANE Select	c.*139dupT		3_prime_UTR	Exon 3 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.*139dupT		3_prime_UTR	Exon 2 of 2	NP_001182551.1	Q9NS56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOPORS	ENST00000360538.7	TSL:1 MANE Select	c.*139dupT		3_prime_UTR	Exon 3 of 3	ENSP00000353735.2	Q9NS56-1
	TOPORS	ENST00000379858.1	TSL:1	c.*139dupT		3_prime_UTR	Exon 2 of 2	ENSP00000369187.1	Q9NS56-2
	ENSG00000288684	ENST00000681750.1		c.-45+9526dupT		intron	N/A	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17637 AN: 148754 Hom.: 1232 Cov.: 29

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0993

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0722

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.139 AC: 86350 AN: 619220 Hom.: 1772 Cov.: 8 AF XY: 0.139 AC XY: 44056 AN XY: 317618

African (AFR) AF: 0.0596 AC: 876 AN: 14688

American (AMR) AF: 0.0920 AC: 1620 AN: 17608

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 3157 AN: 14404

East Asian (EAS) AF: 0.0172 AC: 466 AN: 27058

South Asian (SAS) AF: 0.0824 AC: 3596 AN: 43660

European-Finnish (FIN) AF: 0.148 AC: 4021 AN: 27224

Middle Eastern (MID) AF: 0.213 AC: 471 AN: 2208

European-Non Finnish (NFE) AF: 0.153 AC: 67772 AN: 442372

Other (OTH) AF: 0.146 AC: 4371 AN: 29998

GnomAD4 genome AF: 0.119 AC: 17646 AN: 148850 Hom.: 1232 Cov.: 29 AF XY: 0.116 AC XY: 8418 AN XY: 72486

African (AFR) AF: 0.0538 AC: 2183 AN: 40582

American (AMR) AF: 0.0991 AC: 1475 AN: 14884

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 791 AN: 3446

East Asian (EAS) AF: 0.0153 AC: 78 AN: 5104

South Asian (SAS) AF: 0.0721 AC: 338 AN: 4688

European-Finnish (FIN) AF: 0.147 AC: 1443 AN: 9802

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.161 AC: 10791 AN: 67088

Other (OTH) AF: 0.143 AC: 296 AN: 2066

Alfa AF: 0.0647 Hom.: 63

Bravo AF: 0.112

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis Pigmentosa, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs140010425; hg19: chr9-32541245; COSMIC: COSV62117804;