chr5-78141213-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_003664.5(AP3B1):c.1580G>A(p.Ser527Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S527G) has been classified as Uncertain significance.
Frequency
Consequence
NM_003664.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP3B1 | NM_003664.5 | c.1580G>A | p.Ser527Asn | missense_variant | Exon 15 of 27 | ENST00000255194.11 | NP_003655.3 | |
AP3B1 | NM_001271769.2 | c.1433G>A | p.Ser478Asn | missense_variant | Exon 15 of 27 | NP_001258698.1 | ||
AP3B1 | NM_001410752.1 | c.1580G>A | p.Ser527Asn | missense_variant | Exon 15 of 23 | NP_001397681.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152202Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251228Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135788
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461550Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727070
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome 2 Uncertain:1
This variant has not been reported in the literature in individuals affected with AP3B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505163). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 527 of the AP3B1 protein (p.Ser527Asn). -
not specified Benign:1
p.Ser527Asn in exon 15 of AP3B1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 6 mammals have an asparagine (Asn) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugges t a high likelihood of impact to the protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at