20-41084486-A-C

Variant names:

• chr20-41084486-A-C
• NM_003286.4:c.532A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003286.4(TOP1):​c.532A>C​(p.Asn178His) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOP1 NM_003286.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13380107).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP1	NM_003286.4	c.532A>C	p.Asn178His	missense_variant	Exon 8 of 21	ENST00000361337.3	NP_003277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP1	ENST00000361337.3	c.532A>C	p.Asn178His	missense_variant	Exon 8 of 21	1	NM_003286.4	ENSP00000354522.2
TOP1	ENST00000681058.1	n.686A>C		non_coding_transcript_exon_variant	Exon 8 of 20
TOP1	ENST00000681113.1	n.532A>C		non_coding_transcript_exon_variant	Exon 8 of 23			ENSP00000505788.1
TOP1	ENST00000681392.1	n.1652A>C		non_coding_transcript_exon_variant	Exon 4 of 18

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.532A>C (p.N178H) alteration is located in exon 8 (coding exon 8) of the TOP1 gene. This alteration results from a A to C substitution at nucleotide position 532, causing the asparagine (N) at amino acid position 178 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.079
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.029
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Polyphen		0.41	B
Vest4		0.21
MutPred		0.22		Loss of ubiquitination at K175 (P = 0.0768);
MVP		0.33
MPC		0.80
ClinPred		0.31	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.036

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-39713126;