9-32552436-T-C

Position:

• chr9-32552436-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005802.5(TOPORS):​c.1A>G​(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOPORS NM_005802.5 start_lost, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

Genes affected

SMIM27 (HGNC:31420): (small integral membrane protein 27) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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]

ENSG00000288684 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMIM27	NM_001387564.1	c.2T>C	p.Met1?	start_lost	1/2	ENST00000692500.1	NP_001374493.1
TOPORS	NM_005802.5	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/3	ENST00000360538.7	NP_005793.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMIM27	ENST00000692500.1	c.2T>C	p.Met1?	start_lost	1/2		NM_001387564.1	ENSP00000508648.1
TOPORS	ENST00000360538.7	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/3	1	NM_005802.5	ENSP00000353735.2
ENSG00000288684	ENST00000681750.1	c.-347A>G		splice_region_variant	1/20			ENSP00000506413.1
ENSG00000288684	ENST00000681750.1	c.-347A>G		5_prime_UTR_variant	1/20			ENSP00000506413.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 858769). This variant has not been reported in the literature in individuals affected with TOPORS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the TOPORS mRNA. The next in-frame methionine is located at codon 68. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.66	D;D;D;D
PROVEAN	Benign	-0.23	.;.;N;.
Sift	Pathogenic	0.0	.;.;D;.
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.56
gMVP		0.025

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1821311075; hg19: chr9-32552434;