Genetic Variant TOPORS:c.-64C>A (chr9-32552500-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005802.5(TOPORS):c.-64C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,572,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TOPORS
NM_005802.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.461

Publications

0 publications found

Variant links:

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 links:

ENSG00000288684 (HGNC:):

ENSG00000288684 links:

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

SMIM27 links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.88).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOPORS	NM_005802.5	MANE Select	c.-64C>A	5_prime_UTR	Exon 1 of 3	NP_005793.2
SMIM27	NM_001387564.1	MANE Select	c.45+21G>T	intron	N/A	NP_001374493.1	A0A1B0GUW7
TOPORS	NM_001195622.2		c.-64C>A	5_prime_UTR	Exon 1 of 2	NP_001182551.1	Q9NS56-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOPORS	ENST00000360538.7	TSL:1 MANE Select	c.-64C>A	5_prime_UTR	Exon 1 of 3	ENSP00000353735.2	Q9NS56-1
TOPORS	ENST00000379858.1	TSL:1	c.-64C>A	5_prime_UTR	Exon 1 of 2	ENSP00000369187.1	Q9NS56-2
ENSG00000288684	ENST00000681750.1		c.-411C>A	5_prime_UTR	Exon 1 of 20	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000555

AC:

AN:

180056

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000211

AC:

AN:

1420582

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

703232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32718

American (AMR)

AF:

0.00

AC:

AN:

38656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25554

East Asian (EAS)

AF:

0.00

AC:

AN:

37894

South Asian (SAS)

AF:

0.0000245

AC:

AN:

81786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49680

Middle Eastern (MID)

AF:

0.000230

AC:

AN:

4348

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091272

Other (OTH)

AF:

0.00

AC:

AN:

58674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41504

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

8.0

(source)

DANN

Benign

0.85

PhyloP100

0.46

PromoterAI

-0.0059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over