20-41076256-C-T

Variant names:

• chr20-41076256-C-T
• rs61756255
• NM_003286.4:c.241C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 12/21 in silico tools predict 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31
• Publications: 10 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• 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 VariationId is 777300.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 940 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.241C>T	p.His81Tyr	missense	Exon 4 of 21	NP_003277.1	P11387

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1	ENST00000361337.3	TSL:1 MANE Select	c.241C>T	p.His81Tyr	missense	Exon 4 of 21	ENSP00000354522.2	P11387
	TOP1	ENST00000681058.1		n.395C>T		non_coding_transcript_exon	Exon 4 of 20
	TOP1	ENST00000681113.1		n.241C>T		non_coding_transcript_exon	Exon 4 of 23	ENSP00000505788.1	A0A7P0T9R7

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 940 AN: 152110 Hom.: 5 Cov.: 32

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

GnomAD2 exomes AF: 0.00609 AC: 1512 AN: 248210 AF XY: 0.00619

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 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.: 27 AF XY: 0.0104 AC XY: 7517 AN XY: 723334

African (AFR) AF: 0.00169 AC: 56 AN: 33224

American (AMR) AF: 0.00245 AC: 109 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00312 AC: 268 AN: 85850

European-Finnish (FIN) AF: 0.00337 AC: 180 AN: 53356

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5750

European-Non Finnish (NFE) AF: 0.0129 AC: 14220 AN: 1104536

Other (OTH) AF: 0.00822 AC: 494 AN: 60072

GnomAD4 genome AF: 0.00617 AC: 940 AN: 152228 Hom.: 5 Cov.: 32 AF XY: 0.00563 AC XY: 419 AN XY: 74428

African (AFR) AF: 0.00219 AC: 91 AN: 41546

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10590

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0106 AC: 721 AN: 67998

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00902 Hom.: 15

Bravo AF: 0.00627

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00670 AC: 813

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0108

EpiControl AF: 0.00843

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.071
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Polyphen		0.27	B
Vest4		0.36
MVP		0.25
MPC		0.90
ClinPred		0.061	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.033
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs61756255; hg19: chr20-39704896; COSMIC: COSV99057654;