rs139861201
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004722.4(AP4M1):c.1100G>A(p.Arg367Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000351 in 1,613,738 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. R367W) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.1100G>A | p.Arg367Gln | missense_variant | 14/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.1100G>A | p.Arg367Gln | missense_variant | 14/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000327 AC: 82AN: 250448Hom.: 0 AF XY: 0.000361 AC XY: 49AN XY: 135654
GnomAD4 exome AF: 0.000367 AC: 537AN: 1461492Hom.: 0 Cov.: 35 AF XY: 0.000373 AC XY: 271AN XY: 727036
GnomAD4 genome AF: 0.000197 AC: 30AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74422
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 12, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32979048) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
Hereditary spastic paraplegia 50 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 367 of the AP4M1 protein (p.Arg367Gln). This variant is present in population databases (rs139861201, gnomAD 0.05%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 32979048). ClinVar contains an entry for this variant (Variation ID: 386884). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AP4M1 protein function with a negative predictive value of 80%. 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. - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 15, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at