chr14-31072968-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001128126.3(AP4S1):c.289C>T(p.Arg97Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,462 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001128126.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4S1 | NM_001128126.3 | c.289C>T | p.Arg97Ter | stop_gained | 4/6 | ENST00000542754.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4S1 | ENST00000542754.7 | c.289C>T | p.Arg97Ter | stop_gained | 4/6 | 1 | NM_001128126.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000115 AC: 29AN: 251380Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135880
GnomAD4 exome AF: 0.000115 AC: 168AN: 1461318Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88AN XY: 727024
GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74378
ClinVar
Submissions by phenotype
Spastic paraplegia 52, autosomal recessive Pathogenic:9
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Feb 22, 2019 | [ACMG/AMP: PVS1, PM2, PM3, PP1] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], has been shown to cosegregate with disease in multiple affected family members [PP1]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 10, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris | Jan 06, 2017 | Intellectual disability, moderate; acquired microcephaly (-4SD); hypotonia; epilepsy (starting at 2 months old) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 12, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | Dec 19, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 09, 2023 | Criteria applied: PVS1,PS4_MOD,PM3,PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 02, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25552650, 29302074, 31130284, 32371413, 33644862, 32895917, 32979048, 31345219, 27535533, 28708303) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 29, 2021 | - - |
Spastic paraplegia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 05, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234924). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 25552650). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200440467, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg97*) in the AP4S1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AP4S1 are known to be pathogenic (PMID: 21620353, 25552650, 27444738). - |
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
AP4S1-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Pathogenic and reported on 04-16-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at