rs34348197

Variant names:

• chr14-89956787-C-T
• rs34348197
• NM_018319.4:c.-21C>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.-21C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0735 in 152,300 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (724 hom., cov: 33)
  • Exomes 𝑓: 0.051 (0 hom.)
• Consequence: TDP1 NM_018319.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.637
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-89956787-C-T is Benign according to our data. Variant chr14-89956787-C-T is described in ClinVar as Benign. ClinVar VariationId is 314821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.207 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.-21C>T		5_prime_UTR	Exon 2 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.-8+817C>T		intron	N/A	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.-8+509C>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.-21C>T		5_prime_UTR	Exon 2 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.-21C>T		5_prime_UTR	Exon 2 of 18	ENSP00000377098.3	E7EPD8
	TDP1	ENST00000393454.6	TSL:1	c.-8+817C>T		intron	N/A	ENSP00000377099.2	Q9NUW8-1

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11168 AN: 152102 Hom.: 719 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0798

GnomAD4 exome AF: 0.0513 AC: 4 AN: 78 Hom.: 0 Cov.: 0 AF XY: 0.0517 AC XY: 3 AN XY: 58

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

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

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0200 AC: 1 AN: 50

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.0735 AC: 11194 AN: 152222 Hom.: 724 Cov.: 33 AF XY: 0.0810 AC XY: 6032 AN XY: 74428

African (AFR) AF: 0.0169 AC: 703 AN: 41528

American (AMR) AF: 0.185 AC: 2830 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1037 AN: 5172

South Asian (SAS) AF: 0.218 AC: 1048 AN: 4814

European-Finnish (FIN) AF: 0.0757 AC: 803 AN: 10610

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0641 AC: 4357 AN: 68012

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0675 Hom.: 76

Bravo AF: 0.0788

Asia WGS AF: 0.211 AC: 732 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.79
PhyloP100		0.64
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34348197; hg19: chr14-90423131;