14-89989067-A-G

Variant names:

• chr14-89989067-A-G
• rs202147730
• NM_018319.4:c.1294A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K432Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.07
• Publications: 0 publications found

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]

TDP1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09497836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018319.4. 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
	TDP1	NM_018319.4	MANE Select	c.1294A>G	p.Lys432Glu	missense	Exon 11 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.1294A>G	p.Lys432Glu	missense	Exon 10 of 16	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.1294A>G	p.Lys432Glu	missense	Exon 10 of 15	NP_001317134.1	G3V2F4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	ENST00000335725.9	TSL:1 MANE Select	c.1294A>G	p.Lys432Glu	missense	Exon 11 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393454.6	TSL:1	c.1294A>G	p.Lys432Glu	missense	Exon 10 of 16	ENSP00000377099.2	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.1294A>G	p.Lys432Glu	missense	Exon 11 of 18	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.092
Sift	Benign	0.33	T
Sift4G	Benign	0.81	T
Polyphen		0.0050	B
Vest4		0.26
MutPred		0.40		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
Mutation Taster		=90/10	polymorphism

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: rs202147730; hg19: chr14-90455411;