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GeneBe

20-41084482-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_003286.4(TOP1):c.528C>T(p.Pro176=) 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

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.06
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-41084482-C-T is Benign according to our data. Variant chr20-41084482-C-T is described in ClinVar as [Benign]. Clinvar id is 717596.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.06 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 345 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TOP1NM_003286.4 linkuse as main transcriptc.528C>T p.Pro176= synonymous_variant 8/21 ENST00000361337.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TOP1ENST00000361337.3 linkuse as main transcriptc.528C>T p.Pro176= synonymous_variant 8/211 NM_003286.4 P1
TOP1ENST00000681058.1 linkuse as main transcriptn.682C>T non_coding_transcript_exon_variant 8/20
TOP1ENST00000681392.1 linkuse as main transcriptn.1648C>T non_coding_transcript_exon_variant 4/18
TOP1ENST00000681113.1 linkuse as main transcriptc.528C>T p.Pro176= synonymous_variant, NMD_transcript_variant 8/23

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00227
AC:
345
AN:
151676
Hom.:
2
Cov.:
32
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
GnomAD3 exomes
AF:
0.000499
AC:
98
AN:
196318
Hom.:
1
AF XY:
0.000380
AC XY:
40
AN XY:
105248
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 SAS exome
AF:
0.0000418
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.:
1
Cov.:
28
AF XY:
0.000200
AC XY:
140
AN XY:
700136
show subpopulations
Gnomad4 AFR exome
AF:
0.00790
Gnomad4 AMR exome
AF:
0.000348
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000253
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000331
Gnomad4 OTH exome
AF:
0.000412
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00227
AC:
345
AN:
151796
Hom.:
2
Cov.:
32
AF XY:
0.00231
AC XY:
171
AN XY:
74180
show subpopulations
Gnomad4 AFR
AF:
0.00797
Gnomad4 AMR
AF:
0.000525
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00130
Hom.:
0
Bravo
AF:
0.00247

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 submitterclinical testingInvitaeNov 20, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
Cadd
Benign
12
Dann
Benign
0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

LitVar

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

Other links and lift over

dbSNP: rs149334682; hg19: chr20-39713122; API