NM_018319.4:c.291A>T

Variant names:

• chr14-89963405-A-T
• rs3825663
• NM_018319.4:c.291A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018319.4(TDP1):​c.291A>T​(p.Gln97His) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q97Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• 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, SUPPORTIVE, LIMITED Submitted by: Orphanet, 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051353514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4	c.291A>T	p.Gln97His	missense_variant	Exon 3 of 17	ENST00000335725.9	NP_060789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9	c.291A>T	p.Gln97His	missense_variant	Exon 3 of 17	1	NM_018319.4	ENSP00000337353.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0050
DANN	Benign	0.65
DEOGEN2	Benign	0.0096	.;T;T;T;T;T;T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.60	T;T;.;T;T;T;T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.051	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L;L;.;.;.;.;.
PhyloP100		-2.5
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.36	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.099	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;B;.;.;.;.;B
Vest4		0.052
MutPred		0.13		Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);Gain of catalytic residue at L96 (P = 0.1371);
MVP		0.14
MPC		0.10
ClinPred		0.098	T
GERP RS		-11
PromoterAI		-0.0091	Neutral
Varity_R		0.028
gMVP		0.15
Mutation Taster		=96/4	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: rs3825663; hg19: chr14-90429749;