rs376902371

Variant names:

• chr17-18308367-T-C
• rs376902371
• NM_004618.5:c.298A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004618.5(TOP3A):​c.298A>G​(p.Met100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000705 in 1,602,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: TOP3A NM_004618.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.09
• Publications: 6 publications found

Genes affected

TOP3A (HGNC:11992): (DNA topoisomerase III alpha) 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 reducing the number of supercoils and altering the topology of DNA. This enzyme forms a complex with BLM which functions in the regulation of recombination in somatic cells. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

TOP3A Gene-Disease associations (from GenCC):

• microcephaly, growth restriction, and increased sister chromatid exchange 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-18308367-T-C is Pathogenic according to our data. Variant chr17-18308367-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 446285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03517142). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP3A	NM_004618.5	c.298A>G	p.Met100Val	missense_variant	Exon 3 of 19	ENST00000321105.10	NP_004609.1
TOP3A	XM_047436635.1	c.298A>G	p.Met100Val	missense_variant	Exon 3 of 14		XP_047292591.1
TOP3A	XM_047436634.1	c.-662A>G		5_prime_UTR_variant	Exon 1 of 17		XP_047292590.1
TOP3A	NM_001320759.2	c.29+515A>G		intron_variant	Intron 2 of 17		NP_001307688.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOP3A	ENST00000321105.10	c.298A>G	p.Met100Val	missense_variant	Exon 3 of 19	1	NM_004618.5	ENSP00000321636.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000643 AC: 16 AN: 248744 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000745 AC: 108 AN: 1450608 Hom.: 0 Cov.: 29 AF XY: 0.0000651 AC XY: 47 AN XY: 721768

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.0000227 AC: 1 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39304

South Asian (SAS) AF: 0.00 AC: 0 AN: 84598

European-Finnish (FIN) AF: 0.000339 AC: 18 AN: 53088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000796 AC: 88 AN: 1105058

Other (OTH) AF: 0.0000167 AC: 1 AN: 59732

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151918 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74186

African (AFR) AF: 0.00 AC: 0 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.000190 AC: 2 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial disease Pathogenic:1

Nov 15, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 100 of the TOP3A protein (p.Met100Val). This variant is present in population databases (rs376902371, gnomAD 0.03%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 29290614, 30057030, 37013609). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446285). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TOP3A function (PMID: 29290614). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 Pathogenic:1

Mar 07, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.061	T;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;N;.
PhyloP100		1.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.48	.;N;.
REVEL	Benign	0.054
Sift	Benign	0.36	.;T;.
Sift4G	Benign	0.29	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.22
MVP		0.067
MPC		0.19
ClinPred		0.057	T
GERP RS		4.4
Varity_R		0.091
gMVP		0.19
Mutation Taster		=84/16	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -16

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

Other links and lift over

dbSNP: rs376902371; hg19: chr17-18211681;