NM_005802.5:c.2666A>C

Variant names:

• chr9-32541859-T-G
• NM_005802.5:c.2666A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005802.5(TOPORS):​c.2666A>C​(p.His889Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 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 Lovd as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOPORS NM_005802.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.38

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]

ENSG00000288684 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-32541859-T-G is Pathogenic according to our data. Variant chr9-32541859-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36346143). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOPORS	NM_005802.5	c.2666A>C	p.His889Pro	missense_variant	Exon 3 of 3	ENST00000360538.7	NP_005793.2
TOPORS	NM_001195622.2	c.2471A>C	p.His824Pro	missense_variant	Exon 2 of 2		NP_001182551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOPORS	ENST00000360538.7	c.2666A>C	p.His889Pro	missense_variant	Exon 3 of 3	1	NM_005802.5	ENSP00000353735.2
TOPORS	ENST00000379858.1	c.2471A>C	p.His824Pro	missense_variant	Exon 2 of 2	1		ENSP00000369187.1
ENSG00000288684	ENST00000681750.1	c.-45+8915A>C		intron_variant	Intron 3 of 19			ENSP00000506413.1
ENSG00000288684	ENST00000680198.1	c.198+8915A>C		intron_variant	Intron 2 of 18			ENSP00000505143.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	26
DANN	Uncertain	0.97
DEOGEN2	Benign	0.061	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.061	T;D
Polyphen		1.0	D;.
Vest4		0.54
MutPred		0.16		Gain of glycosylation at H889 (P = 0.0012);.;
MVP		0.24
MPC		0.49
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.26
gMVP		0.28

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-32541857;