14-89955920-GGCC-GGCCGCC

Variant names:

• chr14-89955920-G-GGCC
• rs35210768
• NM_018319.4:c.-276_-274dupCCG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018319.4(TDP1):​c.-276_-274dupCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0729 in 152,408 control chromosomes in the GnomAD database, including 714 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.073 (714 hom., cov: 32)
  • Exomes 𝑓: 0.057 (0 hom.)
• Consequence: TDP1 NM_018319.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.523
• 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, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, 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 -10 ACMG points.

• BP6: Variant 14-89955920-G-GGCC is Benign according to our data. Variant chr14-89955920-G-GGCC is described in ClinVar as Benign. ClinVar VariationId is 314811.Status of the report is criteria_provided_single_submitter, 1 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.-276_-274dupCCG		5_prime_UTR	Exon 1 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.-53_-51dupCCG		5_prime_UTR	Exon 1 of 16	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.-361_-359dupCCG		5_prime_UTR	Exon 1 of 15	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.-276_-274dupCCG		5_prime_UTR	Exon 1 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.-276_-274dupCCG		5_prime_UTR	Exon 1 of 18	ENSP00000377098.3	E7EPD8
	TDP1	ENST00000935815.1		c.-53_-51dupCCG		5_prime_UTR	Exon 1 of 18	ENSP00000605874.1

Frequencies

GnomAD3 genomes AF: 0.0728 AC: 11081 AN: 152164 Hom.: 709 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.0754

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0778

GnomAD4 exome AF: 0.0574 AC: 7 AN: 122 Hom.: 0 Cov.: 0 AF XY: 0.0556 AC XY: 5 AN XY: 90

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

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

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

European-Non Finnish (NFE) AF: 0.0566 AC: 6 AN: 106

Other (OTH) AF: 0.100 AC: 1 AN: 10

GnomAD4 genome AF: 0.0729 AC: 11107 AN: 152286 Hom.: 714 Cov.: 32 AF XY: 0.0804 AC XY: 5990 AN XY: 74468

African (AFR) AF: 0.0162 AC: 673 AN: 41576

American (AMR) AF: 0.184 AC: 2814 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1035 AN: 5174

South Asian (SAS) AF: 0.218 AC: 1053 AN: 4828

European-Finnish (FIN) AF: 0.0754 AC: 800 AN: 10612

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0639 AC: 4344 AN: 68010

Other (OTH) AF: 0.0813 AC: 172 AN: 2116

Alfa AF: 0.0680 Hom.: 56

Asia WGS AF: 0.210 AC: 727 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive cerebellar ataxia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35210768; hg19: chr14-90422264;