7-100106745-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_004722.4(AP4M1):āc.1225T>Cā(p.Phe409Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,696 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F409S) has been classified as Uncertain significance.
Frequency
Consequence
NM_004722.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.1225T>C | p.Phe409Leu | missense_variant | 15/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.1225T>C | p.Phe409Leu | missense_variant | 15/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251142Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135838
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461696Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727164
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 50 Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 409 of the AP4M1 protein (p.Phe409Leu). This variant is present in population databases (rs760907496, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AP4M1-related conditions. ClinVar contains an entry for this variant (Variation ID: 522649). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 25, 2022 | The variant is located in a mutational hot spot and/or critical and well-established functional domain (Adap_comp_sub) - PM1. This variant is not present in population databases (rs760907496- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. The p.(Phe409Leu) was detected in a homozygous state in the analyzed sample - - PM3_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at