14-89956574-G-T

Variant names:

• chr14-89956574-G-T
• rs28365053
• NM_018319.4:c.-230-4G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018319.4(TDP1):​c.-230-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 152,180 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (67 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TDP1 NM_018319.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005797
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.50
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-89956574-G-T is Benign according to our data. Variant chr14-89956574-G-T is described in ClinVar as Benign. ClinVar VariationId is 314816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.057 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TDP1	NM_018319.4	MANE Select	c.-230-4G>T		splice_region intron	N/A	NP_060789.2
	TDP1	NM_001008744.2		c.-8+604G>T		intron	N/A	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.-8+296G>T		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.-230-4G>T		splice_region intron	N/A	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393454.6	TSL:1	c.-8+604G>T		intron	N/A	ENSP00000377099.2	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.-230-4G>T		splice_region intron	N/A	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152062 Hom.: 67 Cov.: 33

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00864

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 100

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 102

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.0172 AC: 2611 AN: 152180 Hom.: 67 Cov.: 33 AF XY: 0.0169 AC XY: 1257 AN XY: 74412

African (AFR) AF: 0.0589 AC: 2446 AN: 41508

American (AMR) AF: 0.00719 AC: 110 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68012

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.00507 Hom.: 1

Bravo AF: 0.0186

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-2.5
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.17
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: rs28365053; hg19: chr14-90422918;