NM_018319.4:c.-224A>G

Variant names:

• chr14-89956584-A-G
• rs35439694
• NM_018319.4:c.-224A>G

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.-224A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0523 in 152,312 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (343 hom., cov: 33)
  • Exomes 𝑓: 0.033 (0 hom.)
• Consequence: TDP1 NM_018319.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.471
• Publications: 1 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=-0.79).
• BP6: Variant 14-89956584-A-G is Benign according to our data. Variant chr14-89956584-A-G is described in ClinVar as Benign. ClinVar VariationId is 314817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.-224A>G		5_prime_UTR	Exon 2 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.-8+614A>G		intron	N/A	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.-8+306A>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.-224A>G		5_prime_UTR	Exon 2 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.-224A>G		5_prime_UTR	Exon 2 of 18	ENSP00000377098.3	E7EPD8
	TDP1	ENST00000393454.6	TSL:1	c.-8+614A>G		intron	N/A	ENSP00000377099.2	Q9NUW8-1

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7957 AN: 152074 Hom.: 343 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0817

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0672

Gnomad FIN AF: 0.0256

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0436

GnomAD4 exome AF: 0.0333 AC: 4 AN: 120 Hom.: 0 Cov.: 0 AF XY: 0.0333 AC XY: 3 AN XY: 90

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

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: 0.0313 AC: 3 AN: 96

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.0524 AC: 7968 AN: 152192 Hom.: 343 Cov.: 33 AF XY: 0.0528 AC XY: 3928 AN XY: 74420

African (AFR) AF: 0.113 AC: 4670 AN: 41504

American (AMR) AF: 0.0531 AC: 812 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0817 AC: 283 AN: 3466

East Asian (EAS) AF: 0.0233 AC: 120 AN: 5146

South Asian (SAS) AF: 0.0672 AC: 324 AN: 4820

European-Finnish (FIN) AF: 0.0256 AC: 272 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1369 AN: 68026

Other (OTH) AF: 0.0469 AC: 99 AN: 2110

Alfa AF: 0.0355 Hom.: 60

Bravo AF: 0.0558

Asia WGS AF: 0.0550 AC: 194 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	-0.79
CADD	Benign	8.1
DANN	Benign	0.63
PhyloP100		0.47
PromoterAI		-0.053	Neutral
Mutation Taster		=300/0	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: rs35439694; hg19: chr14-90422928;