rs575096086
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_004722.4(AP4M1):c.847C>T(p.Arg283Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_004722.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.847C>T | p.Arg283Trp | missense_variant | 11/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.847C>T | p.Arg283Trp | missense_variant | 11/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251432Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135900
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.0000509 AC XY: 37AN XY: 727172
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74440
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 13, 2023 | PM2 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2021 | The c.847C>T (p.R283W) alteration is located in exon 11 (coding exon 11) of the AP4M1 gene. This alteration results from a C to T substitution at nucleotide position 847, causing the arginine (R) at amino acid position 283 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary spastic paraplegia 50 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2021 | This sequence change replaces arginine with tryptophan at codon 283 of the AP4M1 protein (p.Arg283Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs575096086, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with AP4M1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at