rs587776593
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001195248.2(APTX):c.689_690insT(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
Consequence
NM_001195248.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APTX | NM_001195248.2 | c.689_690insT | p.Glu232GlyfsTer38 | frameshift_variant | 6/8 | ENST00000379817.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APTX | ENST00000379817.7 | c.689_690insT | p.Glu232GlyfsTer38 | frameshift_variant | 6/8 | 1 | NM_001195248.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2021 | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2001 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at