chr9-32541016-A-G

Variant names:

• chr9-32541016-A-G
• rs970207555
• NM_005802.5:c.*371T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_005802.5(TOPORS):​c.*371T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 142,938 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TOPORS NM_005802.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000126 (18/142938) while in subpopulation NFE AF = 0.000242 (15/61994). AF 95% confidence interval is 0.000149. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 18 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.*371T>C		3_prime_UTR	Exon 3 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.*371T>C		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.*371T>C		3_prime_UTR	Exon 3 of 3	ENSP00000353735.2	Q9NS56-1
	TOPORS	ENST00000379858.1	TSL:1	c.*371T>C		3_prime_UTR	Exon 2 of 2	ENSP00000369187.1	Q9NS56-2
	ENSG00000288684	ENST00000681750.1		c.-45+9758T>C		intron	N/A	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 18 AN: 142938 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000211

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000242

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000800 AC: 2 AN: 25004 Hom.: 0 Cov.: 0 AF XY: 0.0000743 AC XY: 1 AN XY: 13462

African (AFR) AF: 0.00 AC: 0 AN: 234

American (AMR) AF: 0.00 AC: 0 AN: 2680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 360

East Asian (EAS) AF: 0.00 AC: 0 AN: 1252

South Asian (SAS) AF: 0.00 AC: 0 AN: 3660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 44

European-Non Finnish (NFE) AF: 0.000138 AC: 2 AN: 14470

Other (OTH) AF: 0.00 AC: 0 AN: 1024

GnomAD4 genome AF: 0.000126 AC: 18 AN: 142938 Hom.: 0 Cov.: 32 AF XY: 0.000143 AC XY: 10 AN XY: 69746

African (AFR) AF: 0.00 AC: 0 AN: 40950

American (AMR) AF: 0.0000693 AC: 1 AN: 14420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3188

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4652

European-Finnish (FIN) AF: 0.000211 AC: 2 AN: 9494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.000242 AC: 15 AN: 61994

Other (OTH) AF: 0.00 AC: 0 AN: 1936

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.8
DANN	Benign	0.82
PhyloP100		0.047

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: rs970207555; hg19: chr9-32541014;