rs730882249
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004722.4(AP4M1):c.952C>T(p.Arg318Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,870 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004722.4 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 |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.952C>T | p.Arg318Ter | stop_gained | 12/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.952C>T | p.Arg318Ter | stop_gained | 12/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727236
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 50 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PM2,PM3,(PP1) - |
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
AP4M1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2022 | The AP4M1 c.952C>T variant is predicted to result in premature protein termination (p.Arg318*). This variant was reported in individuals with autosomal recessive spastic tetraplegia (Tüysüz et al. 2014. PubMed ID: 24700674; Table S1, Monies et al. 2019. PubMed ID: 31130284; Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-99703604-C-T). Nonsense variants in AP4M1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hypoplasia of the corpus callosum;C0557874:Global developmental delay;C4025616:CNS hypomyelination;C4551563:Microcephaly;C4551584:Brain atrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at