Variant 20-41076256-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_003286.4(TOP1):c.241C>T(p.His81Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,605,198 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0062 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 131 hom. )

Consequence

TOP1
NM_003286.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.31

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 made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant where missense usually causes diseases, TOP1

BP4

Computational evidence support a benign effect (MetaRNN=0.0068329275).

BP6

Variant 20-41076256-C-T is Benign according to our data. Variant chr20-41076256-C-T is described in ClinVar as [Benign]. Clinvar id is 777300.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 940 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP1	NM_003286.4 linkuse as main transcript	c.241C>T	p.His81Tyr	missense_variant	4/21	ENST00000361337.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TOP1	ENST00000361337.3 linkuse as main transcript	c.241C>T	p.His81Tyr	missense_variant	4/21	1	NM_003286.4	P1
TOP1	ENST00000681058.1 linkuse as main transcript	n.395C>T		non_coding_transcript_exon_variant	4/20
TOP1	ENST00000681392.1 linkuse as main transcript	n.74C>T		non_coding_transcript_exon_variant	1/18
TOP1	ENST00000681113.1 linkuse as main transcript	c.241C>T	p.His81Tyr	missense_variant, NMD_transcript_variant	4/23

Frequencies

GnomAD3 genomes

AF:

0.00618

AC:

940

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00575

GnomAD3 exomes

AF:

0.00609

AC:

1512

AN:

248210

Hom.:

AF XY:

0.00619

AC XY:

832

AN XY:

134336

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00265

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00276

Gnomad FIN exome

AF:

0.00264

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.00687

GnomAD4 exome

AF:

0.0106

AC:

15364

AN:

1452970

Hom.:

131

Cov.:

AF XY:

0.0104

AC XY:

7517

AN XY:

723334

show subpopulations

Gnomad4 AFR exome

AF:

0.00169

Gnomad4 AMR exome

AF:

0.00245

Gnomad4 ASJ exome

AF:

0.00111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00312

Gnomad4 FIN exome

AF:

0.00337

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.00822

GnomAD4 genome

AF:

0.00617

AC:

940

AN:

152228

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00936

Hom.:

Bravo

AF:

0.00627

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00670

AC:

813

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.00843

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.27

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0068

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.3

REVEL

Benign

0.071

Sift

Uncertain

0.0030

Sift4G

Benign

0.13

Polyphen

0.27

Vest4

0.36

MVP

0.25

MPC

0.90

ClinPred

0.061

GERP RS

5.1

Varity_R

0.16

gMVP

0.033

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over