rs138216814
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001253852.3(AP4B1):c.670C>T(p.Arg224Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,611,040 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R224H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001253852.3 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 |
---|---|---|---|---|---|---|---|
AP4B1 | NM_001253852.3 | c.670C>T | p.Arg224Cys | missense_variant | 5/10 | ENST00000369569.6 | |
AP4B1-AS1 | NR_125965.1 | n.1013G>A | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4B1 | ENST00000369569.6 | c.670C>T | p.Arg224Cys | missense_variant | 5/10 | 1 | NM_001253852.3 | P1 | |
AP4B1-AS1 | ENST00000419536.1 | n.845G>A | non_coding_transcript_exon_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000485 AC: 12AN: 247234Hom.: 0 AF XY: 0.0000448 AC XY: 6AN XY: 133810
GnomAD4 exome AF: 0.0000425 AC: 62AN: 1458904Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34AN XY: 725804
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 47 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 224 of the AP4B1 protein (p.Arg224Cys). This variant is present in population databases (rs138216814, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with AP4B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 210196). 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 expected to disrupt AP4B1 protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 20, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at