NM_001195248.2:c.689dupT

Variant names:

• chr9-32984711-C-CA
• rs587776593
• NM_001195248.2:c.689dupT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001195248.2(APTX):​c.689dupT​(p.Glu232GlyfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V230V) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: APTX NM_001195248.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

Genes affected

APTX (HGNC:15984): (aprataxin) This gene encodes a member of the histidine triad (HIT) superfamily. The encoded protein may play a role in single-stranded DNA repair through its nucleotide-binding activity and its diadenosine polyphosphate hydrolase activity. Mutations in this gene have been associated with ataxia-ocular apraxia. Alternatively spliced transcript variants have been identified for this gene.[provided by RefSeq, Aug 2010]

APTX Gene-Disease associations (from GenCC):

• ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-32984711-C-CA is Pathogenic according to our data. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-32984711-C-CA is described in CliVar as Pathogenic. Clinvar id is 4425.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APTX	NM_001195248.2	c.689dupT	p.Glu232GlyfsTer38	frameshift_variant	Exon 6 of 8	ENST00000379817.7	NP_001182177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APTX	ENST00000379817.7	c.689dupT	p.Glu232GlyfsTer38	frameshift_variant	Exon 6 of 8	1	NM_001195248.2	ENSP00000369145.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 22, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689dupT (p.E232Gfs*38) alteration, located in exon 7 (coding exon 5) of the APTX gene, consists of a duplication of T at position 689, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the APTX c.689dupT alteration was not observed, with coverage at this position. The c.689dupT alteration has been reported in multiple patients in either homozygous or compound heterozygous with a second alteration who present with early onset ataxia with oculomotor apraxia, peripheral neuropathy, and hypoalbuminemia. Genotype-phenotype correlations suggest homozygotes are at an increased risk for inability to walk, early ocular motor apraxia onset less than 15 years of age, and cognitive impairment. This alteration has also been reported as c.689insT and c.689_690insT (Hirano, 2004; Ito, 2005: Yokoseki, 2011). Based on the available evidence, this alteration is classified as pathogenic. -

Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia Pathogenic:1

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587776593; hg19: chr9-32984709;