Genetic Variant TOP1:p.Pro176Pro (chr20-41084482-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_003286.4(TOP1):c.528C>T(p.Pro176Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,564,520 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

TOP1
NM_003286.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.06

Publications

0 publications found

Variant links:

Genes affected

TOP1 (HGNC:11986): (DNA topoisomerase I) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus altering the topology of DNA. This gene is localized to chromosome 20 and has pseudogenes which reside on chromosomes 1 and 22. [provided by RefSeq, Jul 2008]

TOP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 20-41084482-C-T is Benign according to our data. Variant chr20-41084482-C-T is described in ClinVar as Benign. ClinVar VariationId is 717596.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.06 with no splicing effect.

BS2

High AC in GnomAd4 at 345 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003286.4. 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
	TOP1	NM_003286.4	MANE Select	c.528C>T	p.Pro176Pro	synonymous	Exon 8 of 21	NP_003277.1	P11387

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP1	ENST00000361337.3	TSL:1 MANE Select	c.528C>T	p.Pro176Pro	synonymous	Exon 8 of 21	ENSP00000354522.2	P11387
TOP1	ENST00000681058.1		n.682C>T		non_coding_transcript_exon	Exon 8 of 20
TOP1	ENST00000681113.1		n.528C>T		non_coding_transcript_exon	Exon 8 of 23	ENSP00000505788.1	A0A7P0T9R7

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

345

AN:

151676

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00800

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000526

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000499

AC:

AN:

196318

AF XY:

0.000380

show subpopulations

Gnomad AFR exome

AF:

0.00692

Gnomad AMR exome

AF:

0.000257

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000236

Gnomad OTH exome

AF:

0.000199

GnomAD4 exome

AF:

0.000228

AC:

322

AN:

1412724

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

140

AN XY:

700136

show subpopulations

African (AFR)

AF:

0.00790

AC:

247

AN:

31262

American (AMR)

AF:

0.000348

AC:

AN:

37328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24886

East Asian (EAS)

AF:

0.00

AC:

AN:

38720

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000331

AC:

AN:

1086188

Other (OTH)

AF:

0.000412

AC:

AN:

58274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00227

AC:

345

AN:

151796

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

171

AN XY:

74180

show subpopulations

African (AFR)

AF:

0.00797

AC:

330

AN:

41382

American (AMR)

AF:

0.000525

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10490

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67924

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00130

Hom.:

Bravo

AF:

0.00247

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.71

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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