14-89989067-A-G

Variant names:

• chr14-89989067-A-G
• NM_018319.4:c.1294A>G

Variant summary

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

The NM_018319.4(TDP1):​c.1294A>G​(p.Lys432Glu) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07

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 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=0.09497836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4	c.1294A>G	p.Lys432Glu	missense_variant	Exon 11 of 17	ENST00000335725.9	NP_060789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9	c.1294A>G	p.Lys432Glu	missense_variant	Exon 11 of 17	1	NM_018319.4	ENSP00000337353.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.15	.;T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.73	T;.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.81	T;T;T;T
Polyphen		0.0050	B;B;B;B
Vest4		0.26
MutPred		0.40		Loss of methylation at K432 (P = 0.0024);Loss of methylation at K432 (P = 0.0024);Loss of methylation at K432 (P = 0.0024);Loss of methylation at K432 (P = 0.0024);
MVP		0.67
MPC		0.16
ClinPred		0.28	T
GERP RS		2.3
Varity_R		0.27
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-90455411;