9-32541247-CAA-CAAAA

Variant names:

• chr9-32541247-C-CAA
• rs140010425
• NM_005802.5:c.*138_*139dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005802.5(TOPORS):​c.*138_*139dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 778,936 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000087 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: TOPORS NM_005802.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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, Labcorp Genetics (formerly Invitae)
• TOPORS-related retinopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288684 (HGNC:):

ACMG classification

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

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000873 (13/148898) while in subpopulation SAS AF = 0.00149 (7/4688). AF 95% confidence interval is 0.0007. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 AD gene.

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.*138_*139dupTT		3_prime_UTR	Exon 3 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.*138_*139dupTT		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.*138_*139dupTT		3_prime_UTR	Exon 3 of 3	ENSP00000353735.2	Q9NS56-1
	TOPORS	ENST00000379858.1	TSL:1	c.*138_*139dupTT		3_prime_UTR	Exon 2 of 2	ENSP00000369187.1	Q9NS56-2
	ENSG00000288684	ENST00000681750.1		c.-45+9525_-45+9526dupTT		intron	N/A	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes AF: 0.0000874 AC: 13 AN: 148802 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000745

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00104 AC: 656 AN: 630038 Hom.: 0 Cov.: 8 AF XY: 0.00102 AC XY: 329 AN XY: 323182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000401 AC: 6 AN: 14964

American (AMR) AF: 0.000333 AC: 6 AN: 18010

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 27 AN: 14642

East Asian (EAS) AF: 0.0000363 AC: 1 AN: 27586

South Asian (SAS) AF: 0.00119 AC: 53 AN: 44584

European-Finnish (FIN) AF: 0.000504 AC: 14 AN: 27762

Middle Eastern (MID) AF: 0.00270 AC: 6 AN: 2226

European-Non Finnish (NFE) AF: 0.00115 AC: 516 AN: 449734

Other (OTH) AF: 0.000884 AC: 27 AN: 30530

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000873 AC: 13 AN: 148898 Hom.: 0 Cov.: 29 AF XY: 0.0000827 AC XY: 6 AN XY: 72512

African (AFR) AF: 0.00 AC: 0 AN: 40588

American (AMR) AF: 0.0000672 AC: 1 AN: 14888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00149 AC: 7 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000745 AC: 5 AN: 67106

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 63

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140010425; hg19: chr9-32541245;