9-32543146-C-G

Variant names:

• chr9-32543146-C-G
• rs146483990
• NM_005802.5:c.1379G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005802.5(TOPORS):​c.1379G>C​(p.Gly460Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G460R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOPORS NM_005802.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.282
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032795727).

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.1379G>C	p.Gly460Ala	missense	Exon 3 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.1184G>C	p.Gly395Ala	missense	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.1379G>C	p.Gly460Ala	missense	Exon 3 of 3	ENSP00000353735.2	Q9NS56-1
	TOPORS	ENST00000379858.1	TSL:1	c.1184G>C	p.Gly395Ala	missense	Exon 2 of 2	ENSP00000369187.1	Q9NS56-2
	ENSG00000288684	ENST00000681750.1		c.-45+7628G>C		intron	N/A	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461756 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727184

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Macular degeneration;C0344232:Blurred vision;C1862475:Abnormality of retinal pigmentation;C4551715:Pigmentary retinopathy (1)
-	1	-	Retinitis pigmentosa 31 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.8
DANN	Benign	0.68
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.28
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.020
Sift	Benign	0.031	D
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.30		Loss of sheet (P = 7e-04)
MVP		0.12
MPC		0.35
ClinPred		0.099	T
GERP RS		2.0
Varity_R		0.037
gMVP		0.18
Mutation Taster		=96/4	polymorphism

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: rs146483990; hg19: chr9-32543144;