14-89966159-C-A

Variant names:

• chr14-89966159-C-A
• rs1555383437
• NM_018319.4:c.572C>A

Variant summary

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

The NM_018319.4(TDP1):​c.572C>A​(p.Pro191His) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.93
• 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: 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	c.572C>A	p.Pro191His	missense_variant	Exon 4 of 17	ENST00000335725.9	NP_060789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TDP1	ENST00000335725.9	c.572C>A	p.Pro191His	missense_variant	Exon 4 of 17	1	NM_018319.4	ENSP00000337353.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453640 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 723786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104676

Other (OTH) AF: 0.00 AC: 0 AN: 60150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	.;T;T;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	.;.;M;.;M;.
PhyloP100		5.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;D;N;D;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.014	D;D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;T;D;T;D
Polyphen		1.0	D;.;D;.;D;D
Vest4		0.63
MutPred		0.44		Loss of ubiquitination at K186 (P = 0.0609);Loss of ubiquitination at K186 (P = 0.0609);Loss of ubiquitination at K186 (P = 0.0609);.;Loss of ubiquitination at K186 (P = 0.0609);Loss of ubiquitination at K186 (P = 0.0609);
MVP		0.42
MPC		0.43
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.59
gMVP		0.61
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555383437; hg19: chr14-90432503;