9-32541717-T-G

Variant names:

• chr9-32541717-T-G
• rs193920910
• NM_005802.5:c.2808A>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.2808A>C​(p.Gln936His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. Q936Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOPORS NM_005802.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.354
• 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: 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=0.061683953).

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.2808A>C	p.Gln936His	missense	Exon 3 of 3	NP_005793.2
	TOPORS	NM_001195622.2		c.2613A>C	p.Gln871His	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.2808A>C	p.Gln936His	missense	Exon 3 of 3	ENSP00000353735.2	Q9NS56-1
	TOPORS	ENST00000379858.1	TSL:1	c.2613A>C	p.Gln871His	missense	Exon 2 of 2	ENSP00000369187.1	Q9NS56-2
	ENSG00000288684	ENST00000681750.1		c.-45+9057A>C		intron	N/A	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.4
DANN	Benign	0.93
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.35
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.072
Sift	Benign	0.11	T
Sift4G	Uncertain	0.042	D
Polyphen		0.0	B
Vest4		0.062
MutPred		0.15		Gain of catalytic residue at N937 (P = 0.0584)
MVP		0.38
MPC		0.29
ClinPred		0.036	T
GERP RS		-1.3
Varity_R		0.043
gMVP		0.15
Mutation Taster		=97/3	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: rs193920910; hg19: chr9-32541715; COSMIC: COSV62117876;