20-41100127-G-T

Variant names:

• chr20-41100127-G-T
• rs6029545
• NM_003286.4:c.1047G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003286.4(TOP1):​c.1047G>T​(p.Arg349Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R349R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOP1 NM_003286.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

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.1047G>T	p.Arg349Ser	missense	Exon 12 of 21	NP_003277.1	P11387
	PLCG1-AS1	NR_109889.1		n.963+531C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP1	ENST00000361337.3	TSL:1 MANE Select	c.1047G>T	p.Arg349Ser	missense	Exon 12 of 21	ENSP00000354522.2	P11387
	PLCG1-AS1	ENST00000454626.1	TSL:1	n.966+531C>A		intron	N/A
	TOP1	ENST00000681058.1		n.5833G>T		non_coding_transcript_exon	Exon 11 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.77
MutPred		0.67		Gain of ubiquitination at K354 (P = 0.0751)
MVP		0.86
MPC		2.4
ClinPred		0.95	D
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.86
Mutation Taster		=5/95	disease causing

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: rs6029545; hg19: chr20-39728767;