rs141832130
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2
The NM_003664.5(AP3B1):c.1022G>A(p.Arg341His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,613,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP3B1 | NM_003664.5 | c.1022G>A | p.Arg341His | missense_variant | Exon 9 of 27 | ENST00000255194.11 | NP_003655.3 | |
AP3B1 | NM_001271769.2 | c.875G>A | p.Arg292His | missense_variant | Exon 9 of 27 | NP_001258698.1 | ||
AP3B1 | NM_001410752.1 | c.1022G>A | p.Arg341His | missense_variant | Exon 9 of 23 | NP_001397681.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000230 AC: 35AN: 152002Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000223 AC: 56AN: 251320Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135816
GnomAD4 exome AF: 0.000490 AC: 716AN: 1460942Hom.: 3 Cov.: 30 AF XY: 0.000466 AC XY: 339AN XY: 726808
GnomAD4 genome AF: 0.000230 AC: 35AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74388
ClinVar
Submissions by phenotype
Hermansky-Pudlak syndrome 2 Uncertain:3
AP3B1 NM_003664.4 exon 9 p.Arg341His (c.1022G>A): This variant has not been reported in the literature but is present in 0.03% (49/129098) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-77473181-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:533468). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 341 of the AP3B1 protein (p.Arg341His). This variant is present in population databases (rs141832130, gnomAD 0.04%). 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: 533468). 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: "Possibly 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. -
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not provided Uncertain:3
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not specified Uncertain:1
Variant summary: AP3B1 c.1022G>A (p.Arg341His) results in a non-conservative amino acid change located in the Clathrin/coatomer adaptor, adaptin-like, N-terminal domain (IPR002553) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 251320 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome (0.00022 vs 0.0005), allowing no conclusion about variant significance. c.1022G>A has been reported in the literature in one individual affected with NK/T-cell lymphoma of nasal type (example, Guan_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hermansky-Pudlak Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34170459). ClinVar contains an entry for this variant (Variation ID: 533468). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at