Genetic Variant TDP1:p.Pro191Arg (chr14-89966159-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018319.4(TDP1):c.572C>G(p.Pro191Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,640 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P191L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.93

Publications

0 publications found

Variant links:

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

TDP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TDP1	NM_018319.4 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 4 of 17	ENST00000335725.9	NP_060789.2	Q9NUW8-1A0A024R6L5B3KN41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9 link	c.572C>G	p.Pro191Arg	missense_variant	Exon 4 of 17	1	NM_018319.4	ENSP00000337353.4		Q9NUW8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.0000224

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104676

Other (OTH)

AF:

0.00

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

.;T;T;.;T;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;.;D;D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;.;M;.;M;.

PhyloP100

5.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.5

N;D;N;D;N;N

REVEL

Benign

0.29

Sift

Benign

0.14

T;D;D;D;D;T

Sift4G

Benign

0.14

T;D;T;D;T;T

Polyphen

1.0

D;.;D;.;D;D

Vest4

0.69

MutPred

0.49

Gain of MoRF binding (P = 0.0488);Gain of MoRF binding (P = 0.0488);Gain of MoRF binding (P = 0.0488);.;Gain of MoRF binding (P = 0.0488);Gain of MoRF binding (P = 0.0488);

MVP

0.34

MPC

0.54

ClinPred

0.98

GERP RS

5.5

Varity_R

0.45

gMVP

0.68

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over