rs4142394

Variant names:

• chr20-41108082-T-C
• rs4142394
• NM_003286.4:c.1309-4700T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003286.4(TOP1):​c.1309-4700T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,246 control chromosomes in the GnomAD database, including 2,134 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (2134 hom., cov: 32)
• Consequence: TOP1 NM_003286.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 6 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]

PLCG1-AS1 (HGNC:40450): (PLCG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1	NM_003286.4	c.1309-4700T>C		intron_variant	Intron 13 of 20	ENST00000361337.3	NP_003277.1
PLCG1-AS1	NR_109889.1	n.711-6793A>G		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1	ENST00000361337.3	c.1309-4700T>C		intron_variant	Intron 13 of 20	1	NM_003286.4	ENSP00000354522.2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17844 AN: 152128 Hom.: 2131 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0972

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.117 AC: 17876 AN: 152246 Hom.: 2134 Cov.: 32 AF XY: 0.120 AC XY: 8955 AN XY: 74446

African (AFR) AF: 0.257 AC: 10658 AN: 41520

American (AMR) AF: 0.131 AC: 2010 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2424 AN: 5174

South Asian (SAS) AF: 0.0653 AC: 315 AN: 4824

European-Finnish (FIN) AF: 0.0538 AC: 571 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0226 AC: 1534 AN: 68022

Other (OTH) AF: 0.0962 AC: 203 AN: 2110

Alfa AF: 0.0580 Hom.: 2388

Bravo AF: 0.135

Asia WGS AF: 0.182 AC: 633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		-0.018
Mutation Taster		=100/0	polymorphism (auto)

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: rs4142394; hg19: chr20-39736722;