rs376478015
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001253852.3(AP4B1):c.577G>A(p.Val193Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001253852.3 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 |
---|---|---|---|---|---|---|---|
AP4B1 | NM_001253852.3 | c.577G>A | p.Val193Ile | missense_variant | 4/10 | ENST00000369569.6 | |
AP4B1-AS1 | NR_125965.1 | downstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP4B1 | ENST00000369569.6 | c.577G>A | p.Val193Ile | missense_variant | 4/10 | 1 | NM_001253852.3 | P1 | |
AP4B1-AS1 | ENST00000419536.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251488Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135918
GnomAD4 exome AF: 0.000128 AC: 187AN: 1461876Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88AN XY: 727242
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74312
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 47 Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 08, 2013 | - - |
Pathogenic, criteria provided, single submitter | research | Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) | Apr 27, 2023 | - - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Oct 01, 2020 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2021 | The c.577G>A (p.V193I) alteration is located in exon 5 (coding exon 4) of the AP4B1 gene. This alteration results from a G to A substitution at nucleotide position 577, causing the valine (V) at amino acid position 193 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2021 | Reported in a patient with intellectual disability who also harbored a second AP4B1 variant, although the analysis did not determine if the variants were on the same (in cis) or opposite (in trans) chromosomes (Lamichhane et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29193663, 32285480, 25552650, 25693842, 27625858, 27535533, 32979048, 29430868) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at