Genetic Variant TOP1MT:p.Arg585Gln (chr8-143309493-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_052963.3(TOP1MT):c.1754G>A(p.Arg585Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000304 in 1,614,044 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R585W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

TOP1MT
NM_052963.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.81

Publications

6 publications found

Variant links:

Genes affected

TOP1MT (HGNC:29787): (DNA topoisomerase I mitochondrial) This gene encodes a mitochondrial DNA topoisomerase that plays a role in the modification of DNA topology. The encoded protein is a type IB topoisomerase and catalyzes the transient breaking and rejoining of DNA to relieve tension and DNA supercoiling generated in the mitochondrial genome during replication and transcription. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

TOP1MT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01945725).

BP6

Variant 8-143309493-C-T is Benign according to our data. Variant chr8-143309493-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1647906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052963.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP1MT	NM_052963.3	MANE Select	c.1754G>A	p.Arg585Gln	missense	Exon 14 of 14	NP_443195.1	Q969P6-1
TOP1MT	NM_001258446.1		c.1460G>A	p.Arg487Gln	missense	Exon 15 of 15	NP_001245375.1	Q969P6-2
TOP1MT	NM_001258447.1		c.1460G>A	p.Arg487Gln	missense	Exon 14 of 14	NP_001245376.1	Q969P6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP1MT	ENST00000329245.9	TSL:1 MANE Select	c.1754G>A	p.Arg585Gln	missense	Exon 14 of 14	ENSP00000328835.3	Q969P6-1
TOP1MT	ENST00000969804.1		c.1844G>A	p.Arg615Gln	missense	Exon 14 of 14	ENSP00000639863.1
TOP1MT	ENST00000870174.1		c.1799G>A	p.Arg600Gln	missense	Exon 14 of 14	ENSP00000540233.1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000426

AC:

107

AN:

251284

AF XY:

0.000420

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000219

AC:

320

AN:

1461712

Hom.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.00373

AC:

125

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1112004

Other (OTH)

AF:

0.000265

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

101

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:

0.00112

AC:

170

AN:

152332

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00370

AC:

154

AN:

41570

American (AMR)

AF:

0.000327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000451

Hom.:

Bravo

AF:

0.00125

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

3.0

PhyloP100

6.8

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.28

Sift

Uncertain

0.025

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.62

MVP

0.66

MPC

0.69

ClinPred

0.13

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.24

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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