rs3825663

Variant names:

• chr14-89963405-A-G
• rs3825663
• NM_018319.4:c.291A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-89963405-A-G
• chr14-89963405-A-C
• chr14-89963405-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018319.4(TDP1):​c.291A>G​(p.Gln97Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0814 in 1,614,036 control chromosomes in the GnomAD database, including 22,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (10970 hom., cov: 32)
  • Exomes 𝑓: 0.065 (11844 hom.)
• Consequence: TDP1 NM_018319.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.46
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-89963405-A-G is Benign according to our data. Variant chr14-89963405-A-G is described in ClinVar as Benign. ClinVar VariationId is 314824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.704 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.291A>G	p.Gln97Gln	synonymous	Exon 3 of 17	NP_060789.2
	TDP1	NM_001008744.2		c.291A>G	p.Gln97Gln	synonymous	Exon 2 of 16	NP_001008744.1	Q9NUW8-1
	TDP1	NM_001330205.2		c.291A>G	p.Gln97Gln	synonymous	Exon 2 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.291A>G	p.Gln97Gln	synonymous	Exon 3 of 17	ENSP00000337353.4	Q9NUW8-1
	TDP1	ENST00000393454.6	TSL:1	c.291A>G	p.Gln97Gln	synonymous	Exon 2 of 16	ENSP00000377099.2	Q9NUW8-1
	TDP1	ENST00000393452.7	TSL:1	c.291A>G	p.Gln97Gln	synonymous	Exon 3 of 18	ENSP00000377098.3	E7EPD8

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36118 AN: 152088 Hom.: 10932 Cov.: 32

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0386

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.104 AC: 26107 AN: 251322 AF XY: 0.0933

Gnomad AFR exome AF: 0.727

Gnomad AMR exome AF: 0.0894

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0433

Gnomad OTH exome AF: 0.0799

GnomAD4 exome AF: 0.0651 AC: 95219 AN: 1461830 Hom.: 11844 Cov.: 35 AF XY: 0.0644 AC XY: 46848 AN XY: 727224

African (AFR) AF: 0.743 AC: 24880 AN: 33478

American (AMR) AF: 0.0930 AC: 4160 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3335 AN: 26126

East Asian (EAS) AF: 0.0297 AC: 1181 AN: 39700

South Asian (SAS) AF: 0.104 AC: 9011 AN: 86258

European-Finnish (FIN) AF: 0.0390 AC: 2083 AN: 53418

Middle Eastern (MID) AF: 0.148 AC: 854 AN: 5768

European-Non Finnish (NFE) AF: 0.0393 AC: 43702 AN: 1111964

Other (OTH) AF: 0.0996 AC: 6013 AN: 60396

GnomAD4 genome AF: 0.238 AC: 36220 AN: 152206 Hom.: 10970 Cov.: 32 AF XY: 0.230 AC XY: 17126 AN XY: 74442

African (AFR) AF: 0.711 AC: 29468 AN: 41454

American (AMR) AF: 0.132 AC: 2028 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.0289 AC: 150 AN: 5182

South Asian (SAS) AF: 0.103 AC: 499 AN: 4826

European-Finnish (FIN) AF: 0.0386 AC: 410 AN: 10622

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0413 AC: 2808 AN: 68024

Other (OTH) AF: 0.185 AC: 392 AN: 2114

Alfa AF: 0.108 Hom.: 11594

Bravo AF: 0.265

Asia WGS AF: 0.119 AC: 417 AN: 3478

EpiCase AF: 0.0487

EpiControl AF: 0.0471

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.058
DANN	Benign	0.30
PhyloP100		-2.5
PromoterAI		-0.0068	Neutral
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: rs3825663; hg19: chr14-90429749; COSMIC: COSV59643458;