rs387906838
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_004722.4(AP4M1):c.577G>A(p.Glu193Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,908 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).
Frequency
Consequence
NM_004722.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP4M1 | NM_004722.4 | c.577G>A | p.Glu193Lys | missense_variant | 7/15 | ENST00000359593.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4M1 | ENST00000359593.9 | c.577G>A | p.Glu193Lys | missense_variant | 7/15 | 1 | NM_004722.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727214
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74268
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 50 Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 21, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 07, 2018 | 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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to segregate with microcephaly, intellectual disability and spastic paraplegia in an affected family (PMID: 21937992). ClinVar contains an entry for this variant (Variation ID: 30264). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 193 of the AP4M1 protein (p.Glu193Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
AP-4 deficiency syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Aug 02, 2022 | Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine (exon 7). (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif that does not have a well established function. (N) 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in multiple unrelated homozygous individuals with spastic paraplegia 50 (ClinVar, PMID:21937992, PMID:31359954, PMID:29302074). (P) 0903 - Low evidence for segregation in a family with disease (PMID:29302074). (P) 1007 - No published functional evidence has been identified for this variant. (N) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at