chr14-90033208-A-G

Variant names:

• chr14-90033208-A-G
• rs201355368
• NM_018319.4:c.1747A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_018319.4(TDP1):​c.1747A>G​(p.Ser583Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,582,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.83
• Publications: 2 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 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1747A>G	p.Ser583Gly	missense	Exon 16 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.1747A>G	p.Ser583Gly	missense	Exon 15 of 16	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.1645-9862A>G		intron	N/A	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.1747A>G	p.Ser583Gly	missense	Exon 16 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393454.6	TSL:1	c.1747A>G	p.Ser583Gly	missense	Exon 15 of 16	ENSP00000377099.2	Q9NUW8-1
	TDP1	ENST00000556063.1	TSL:1	c.667A>G	p.Ser223Gly	missense	Exon 7 of 7	ENSP00000450795.1	H0YJ44

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152130 Hom.: 0 Cov.: 32

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: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 88 AN: 250966 AF XY: 0.000347

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000227 AC: 325 AN: 1429996 Hom.: 0 Cov.: 25 AF XY: 0.000240 AC XY: 171 AN XY: 713334

African (AFR) AF: 0.00 AC: 0 AN: 32810

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85568

European-Finnish (FIN) AF: 0.00217 AC: 116 AN: 53404

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.000178 AC: 193 AN: 1083076

Other (OTH) AF: 0.000253 AC: 15 AN: 59274

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.055
Sift	Benign	0.11	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.23
MVP		0.67
MPC		0.099
ClinPred		0.032	T
GERP RS		1.8
Varity_R		0.20
gMVP		0.19
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201355368; hg19: chr14-90499552;