20-41100127-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_003286.4(TOP1):c.1047G>A(p.Arg349=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,886 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (13 hom.)
• Consequence: TOP1 NM_003286.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 20-41100127-G-A is Benign according to our data. Variant chr20-41100127-G-A is described in ClinVar as [Benign]. Clinvar id is 783862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00778 (1184/152266) while in subpopulation AFR AF= 0.027 (1121/41536). AF 95% confidence interval is 0.0257. There are 11 homozygotes in gnomad4. There are 547 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOP1	NM_003286.4	c.1047G>A	p.Arg349=	synonymous_variant	12/21	ENST00000361337.3
PLCG1-AS1	NR_109889.1	n.963+531C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOP1	ENST00000361337.3	c.1047G>A	p.Arg349=	synonymous_variant	12/21	1	NM_003286.4	P1
PLCG1-AS1	ENST00000454626.1	n.966+531C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152148 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.0000735

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00201 AC: 504 AN: 251192 Hom.: 6 AF XY: 0.00153 AC XY: 208 AN XY: 135760

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000795 AC: 1162 AN: 1461620 Hom.: 13 Cov.: 30 AF XY: 0.000689 AC XY: 501 AN XY: 727152

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00778 AC: 1184 AN: 152266 Hom.: 11 Cov.: 32 AF XY: 0.00735 AC XY: 547 AN XY: 74462

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00329 Hom.: 1

Bravo AF: 0.00890

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	7.8
Dann	Benign	0.87

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

Other links and lift over

dbSNP: rs6029545; hg19: chr20-39728767; COSMIC: COSV100794041;