rs1555387536

Positions:

• chr14-89984610-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018319.4(TDP1):​c.979T>G​(p.Leu327Val) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L327L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

Genes affected

TDP1 (HGNC:18884): (tyrosyl-DNA phosphodiesterase 1) The protein encoded by this gene is involved in repairing stalled topoisomerase I-DNA complexes by catalyzing the hydrolysis of the phosphodiester bond between the tyrosine residue of topoisomerase I and the 3-prime phosphate of DNA. This protein may also remove glycolate from single-stranded DNA containing 3-prime phosphoglycolate, suggesting a role in repair of free-radical mediated DNA double-strand breaks. This gene is a member of the phospholipase D family and contains two PLD phosphodiesterase domains. Mutations in this gene are associated with the disease spinocerebellar ataxia with axonal neuropathy (SCAN1). [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TDP1	NM_018319.4	c.979T>G	p.Leu327Val	missense_variant	9/17	ENST00000335725.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TDP1	ENST00000335725.9	c.979T>G	p.Leu327Val	missense_variant	9/17	1	NM_018319.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	.;D;D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	3.0	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.052	T;T;T;T
Sift4G	Benign	0.068	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.91
MutPred		0.81		Gain of catalytic residue at L327 (P = 0.0112);Gain of catalytic residue at L327 (P = 0.0112);Gain of catalytic residue at L327 (P = 0.0112);Gain of catalytic residue at L327 (P = 0.0112);
MVP		0.70
MPC		0.51
ClinPred		0.94	D
GERP RS		-1.2
Varity_R		0.26
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1555387536; hg19: chr14-90450954;