Genetic Variant TOPORS:c.-61G>A (chr9-32552497-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_005802.5(TOPORS):c.-61G>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 0.00117 in 1,575,322 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

TOPORS
NM_005802.5 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.58

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 9-32552497-C-T is Benign according to our data. Variant chr9-32552497-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 976633.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000979 (149/152182) while in subpopulation AMR AF = 0.00268 (41/15296). AF 95% confidence interval is 0.00203. There are 1 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 149 AD gene.

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.-61G>A	5_prime_UTR	Exon 1 of 3	NP_005793.2
SMIM27	NM_001387564.1	MANE Select	c.45+18C>T	intron	N/A	NP_001374493.1	A0A1B0GUW7
TOPORS	NM_001195622.2		c.-61G>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.-61G>A	5_prime_UTR	Exon 1 of 3	ENSP00000353735.2	Q9NS56-1
TOPORS	ENST00000379858.1	TSL:1	c.-61G>A	5_prime_UTR	Exon 1 of 2	ENSP00000369187.1	Q9NS56-2
ENSG00000288684	ENST00000681750.1		c.-408G>A	5_prime_UTR	Exon 1 of 20	ENSP00000506413.1	A0A7P0TB70

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00480

GnomAD2 exomes

AF:

0.00107

AC:

197

AN:

183652

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.000301

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000237

Gnomad NFE exome

AF:

0.00162

Gnomad OTH exome

AF:

0.00183

GnomAD4 exome

AF:

0.00119

AC:

1695

AN:

1423140

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

827

AN XY:

704642

show subpopulations

African (AFR)

AF:

0.000183

AC:

AN:

32758

American (AMR)

AF:

0.00166

AC:

AN:

39042

Ashkenazi Jewish (ASJ)

AF:

0.0000391

AC:

AN:

25574

East Asian (EAS)

AF:

0.00

AC:

AN:

38058

South Asian (SAS)

AF:

0.000804

AC:

AN:

82078

European-Finnish (FIN)

AF:

0.000542

AC:

AN:

49836

Middle Eastern (MID)

AF:

0.000229

AC:

AN:

4370

European-Non Finnish (NFE)

AF:

0.00132

AC:

1447

AN:

1092660

Other (OTH)

AF:

0.00140

AC:

AN:

58764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.000979

AC:

149

AN:

152182

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41524

American (AMR)

AF:

0.00268

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000832

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

67980

Other (OTH)

AF:

0.00475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.00125

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.3

(source)

DANN

Benign

0.89

PhyloP100

-2.6

PromoterAI

0.0078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism

(source)

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over