rs876661295
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000542754.7(AP4S1):c.137_138+2delAAGT(p.Gln46fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000542754.7 frameshift, splice_donor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251148Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135812
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461654Hom.: 0 AF XY: 0.0000124 AC XY: 9AN XY: 727126
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Spastic paraplegia 52, autosomal recessive Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Oct 28, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 21, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Jan 24, 2022 | PM2, PP3, PP5 - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
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 | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2023 | Non-canonical splice site variant demonstrated to result in loss-of-function as mRNA levels were virtually absent in the samples from affected individuals homozygous for c.1383_138+6delAAGT (Tessa et al., 2016); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31915823, 30293248, 27444738, 28150420, 25552650, 30552426) - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 05, 2023 | This sequence change falls in intron 2 of the AP4S1 gene. It does not directly change the encoded amino acid sequence of the AP4S1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs758873371, gnomAD 0.004%). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 234925). This variant is also known as c.137_140delAAGT. This variant has been observed in individual(s) with AP4S1-related conditions (PMID: 25552650, 27444738, 28150420). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.138+3_138+6delAAGT intronic variant, also known as c.137_140delAAGT, is located 3 nucleotides after coding exon 1 in the AP4S1 gene. This variant results from a deletion of 4 nucleotides at positions c.138+3 to c.138+6. The stop codon in the predicted resulting transcript occurs in the 5' end of the AP4S1 gene. As such, this alteration may escape nonsense-mediated mRNA decay and/or be prone to rescue by reinitation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the AP4S1 c.138+3_138+6delAAGT alteration was observed in <0.01% (4/251148) of total alleles studied, with a frequency of <0.01% (4/113592) in the European (non-Finnish) subpopulation. This variant was detected as homozygous and compound heterozygous in multiple individuals with spastic paraplegia, intellectual disability, early-onset seizures, and other neurological findings consistent with AP4S1-related spastic parapelgia (Hardies, 2015; Tessa, 2016; Vill, 2017; Papuc, 2019). This nucleotide region is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. - |
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Feb 24, 2021 | - - |
Intellectual disability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
APS41-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