14-89989844-G-T

Variant names:

• chr14-89989844-G-T
• rs2401863
• NM_018319.4:c.1366+79G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018319.4(TDP1):​c.1366+79G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,112,574 control chromosomes in the GnomAD database, including 226,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37213 hom., cov: 32)
  • Exomes 𝑓: 0.62 (189618 hom.)
• Consequence: TDP1 NM_018319.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.170
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-89989844-G-T is Benign according to our data. Variant chr14-89989844-G-T is described in ClinVar as Benign. ClinVar VariationId is 1278564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

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.1366+79G>T		intron	N/A	NP_060789.2
	TDP1	NM_001008744.2		c.1366+79G>T		intron	N/A	NP_001008744.1
	TDP1	NM_001330205.2		c.1366+79G>T		intron	N/A	NP_001317134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	ENST00000335725.9	TSL:1 MANE Select	c.1366+79G>T		intron	N/A	ENSP00000337353.4
	TDP1	ENST00000393454.6	TSL:1	c.1366+79G>T		intron	N/A	ENSP00000377099.2
	TDP1	ENST00000393452.7	TSL:1	c.1366+79G>T		intron	N/A	ENSP00000377098.3

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104343 AN: 151942 Hom.: 37155 Cov.: 32

Gnomad AFR AF: 0.887

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.652

GnomAD4 exome AF: 0.623 AC: 598786 AN: 960514 Hom.: 189618 AF XY: 0.628 AC XY: 312490 AN XY: 497820

African (AFR) AF: 0.898 AC: 21529 AN: 23974

American (AMR) AF: 0.639 AC: 26881 AN: 42094

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 15076 AN: 22888

East Asian (EAS) AF: 0.466 AC: 17265 AN: 37054

South Asian (SAS) AF: 0.760 AC: 56916 AN: 74924

European-Finnish (FIN) AF: 0.652 AC: 34254 AN: 52534

Middle Eastern (MID) AF: 0.667 AC: 3221 AN: 4828

European-Non Finnish (NFE) AF: 0.602 AC: 396167 AN: 658414

Other (OTH) AF: 0.627 AC: 27477 AN: 43804

GnomAD4 genome AF: 0.687 AC: 104464 AN: 152060 Hom.: 37213 Cov.: 32 AF XY: 0.686 AC XY: 51006 AN XY: 74326

African (AFR) AF: 0.887 AC: 36828 AN: 41502

American (AMR) AF: 0.620 AC: 9453 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2307 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2161 AN: 5172

South Asian (SAS) AF: 0.747 AC: 3600 AN: 4820

European-Finnish (FIN) AF: 0.652 AC: 6870 AN: 10542

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.604 AC: 41074 AN: 67982

Other (OTH) AF: 0.653 AC: 1377 AN: 2110

Alfa AF: 0.649 Hom.: 25700

Bravo AF: 0.693

Asia WGS AF: 0.637 AC: 2218 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Apr 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs2401863; hg19: chr14-90456188;