7-4783361-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_014855.3(AP5Z1):c.412C>T(p.Arg138Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_014855.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP5Z1 | NM_014855.3 | c.412C>T | p.Arg138Ter | stop_gained | 4/17 | ENST00000649063.2 | |
AP5Z1 | XM_047421098.1 | c.76C>T | p.Arg26Ter | stop_gained | 2/15 | ||
AP5Z1 | NM_001364858.1 | c.-57C>T | 5_prime_UTR_variant | 3/16 | |||
AP5Z1 | NR_157345.1 | n.505C>T | non_coding_transcript_exon_variant | 4/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP5Z1 | ENST00000649063.2 | c.412C>T | p.Arg138Ter | stop_gained | 4/17 | NM_014855.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247374Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 134618
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1460828Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 726714
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152018Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74256
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 48 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 06, 2023 | This sequence change creates a premature translational stop signal (p.Arg138*) in the AP5Z1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP5Z1 are known to be pathogenic (PMID: 20613862, 27606357). This variant is present in population databases (rs778457903, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with spastic paraplegia (PMID: 24833714, 27606357). ClinVar contains an entry for this variant (Variation ID: 375314). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The AP5Z1 c.412C>T (p.Arg138Ter) variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for recessive spastic paraplegia. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at