NM_018319.4:c.148G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_018319.4(TDP1):​c.148G>A​(p.Glu50Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,614,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TDP1
NM_018319.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.84

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30739555).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TDP1NM_018319.4 linkc.148G>A p.Glu50Lys missense_variant Exon 3 of 17 ENST00000335725.9 NP_060789.2 Q9NUW8-1A0A024R6L5B3KN41

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TDP1ENST00000335725.9 linkc.148G>A p.Glu50Lys missense_variant Exon 3 of 17 1 NM_018319.4 ENSP00000337353.4 Q9NUW8-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251470
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461882
Hom.:
0
Cov.:
34
AF XY:
0.0000110
AC XY:
8
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000135
AC:
15
AN:
1112000
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.480
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74444
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41532
American (AMR)
AF:
0.00
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Dec 27, 2017
Athena Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.026
.;T;T;T;T;T;T;.;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;D;.;D;D;D;D;D;D
M_CAP
Benign
0.025
T
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.8
.;.;M;M;.;.;.;.;.
PhyloP100
6.8
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.1
N;N;N;N;D;D;D;D;N
REVEL
Benign
0.12
Sift
Uncertain
0.013
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.053
T;D;T;T;D;D;D;D;T
Polyphen
0.99
D;.;D;D;.;.;.;.;D
Vest4
0.18
MutPred
0.33
Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);Gain of MoRF binding (P = 0.0035);
MVP
0.44
MPC
0.36
ClinPred
0.92
D
GERP RS
5.5
PromoterAI
0.0078
Neutral
Varity_R
0.14
gMVP
0.33
Mutation Taster
=250/50
polymorphism

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

Other links and lift over

dbSNP: rs781564388; hg19: chr14-90429606; API