14-89963399-G-T

Variant names:

• chr14-89963399-G-T
• rs35114462
• NM_018319.4:c.285G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_018319.4(TDP1):​c.285G>T​(p.Glu95Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,614,212 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: TDP1 NM_018319.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.233
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002392292).
• BP6: Variant 14-89963399-G-T is Benign according to our data. Variant chr14-89963399-G-T is described in ClinVar as Benign. ClinVar VariationId is 448655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	NM_018319.4	MANE Select	c.285G>T	p.Glu95Asp	missense	Exon 3 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.285G>T	p.Glu95Asp	missense	Exon 2 of 16	NP_001008744.1
	TDP1	NM_001330205.2		c.285G>T	p.Glu95Asp	missense	Exon 2 of 15	NP_001317134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	ENST00000335725.9	TSL:1 MANE Select	c.285G>T	p.Glu95Asp	missense	Exon 3 of 17	ENSP00000337353.4
	TDP1	ENST00000393454.6	TSL:1	c.285G>T	p.Glu95Asp	missense	Exon 2 of 16	ENSP00000377099.2
	TDP1	ENST00000393452.7	TSL:1	c.285G>T	p.Glu95Asp	missense	Exon 3 of 18	ENSP00000377098.3

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00905

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000648 AC: 163 AN: 251372 AF XY: 0.000368

Gnomad AFR exome AF: 0.00911

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000238 AC: 348 AN: 1461862 Hom.: 1 Cov.: 34 AF XY: 0.000173 AC XY: 126 AN XY: 727236

African (AFR) AF: 0.00884 AC: 296 AN: 33478

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111992

Other (OTH) AF: 0.000580 AC: 35 AN: 60396

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74506

African (AFR) AF: 0.00902 AC: 375 AN: 41578

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000781 Hom.: 9

Bravo AF: 0.00309

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000898 AC: 109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

May 09, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.23
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.066
Sift	Benign	0.15	T
Sift4G	Benign	0.17	T
Polyphen		0.073	B
Vest4		0.20
MutPred		0.076		Loss of helix (P = 0.2662)
MVP		0.36
MPC		0.12
ClinPred		0.014	T
GERP RS		2.4
PromoterAI		0.013	Neutral
Varity_R		0.047
gMVP		0.084
Mutation Taster		=292/8	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: rs35114462; hg19: chr14-90429743;