rs148817957
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_007347.5(AP4E1):āc.1276A>Cā(p.Ile426Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,014 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0011 ( 0 hom., cov: 32)
Exomes š: 0.0016 ( 3 hom. )
Consequence
AP4E1
NM_007347.5 missense
NM_007347.5 missense
Scores
1
4
14
Clinical Significance
Conservation
PhyloP100: 8.95
Genes affected
AP4E1 (HGNC:573): (adaptor related protein complex 4 subunit epsilon 1) This gene encodes a member of the adaptor complexes large subunit protein family. These proteins are components of the heterotetrameric adaptor protein complexes, which play important roles in the secretory and endocytic pathways by mediating vesicle formation and sorting of integral membrane proteins. The encoded protein is a large subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Disruption of this gene may be associated with cerebral palsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.023585916).
BP6
Variant 15-50948119-A-C is Benign according to our data. Variant chr15-50948119-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432244.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00106 (162/152364) while in subpopulation NFE AF= 0.00201 (137/68032). AF 95% confidence interval is 0.00174. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AP4E1 | NM_007347.5 | c.1276A>C | p.Ile426Leu | missense_variant | 11/21 | ENST00000261842.10 | NP_031373.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AP4E1 | ENST00000261842.10 | c.1276A>C | p.Ile426Leu | missense_variant | 11/21 | 1 | NM_007347.5 | ENSP00000261842.5 | ||
AP4E1 | ENST00000560508.1 | c.1051A>C | p.Ile351Leu | missense_variant | 11/21 | 1 | ENSP00000452976.1 | |||
AP4E1 | ENST00000558439.5 | n.*398A>C | non_coding_transcript_exon_variant | 11/21 | 1 | ENSP00000452712.1 | ||||
AP4E1 | ENST00000561393.5 | n.*320A>C | non_coding_transcript_exon_variant | 10/20 | 1 | ENSP00000452711.1 | ||||
AP4E1 | ENST00000558439.5 | n.*398A>C | 3_prime_UTR_variant | 11/21 | 1 | ENSP00000452712.1 | ||||
AP4E1 | ENST00000561393.5 | n.*320A>C | 3_prime_UTR_variant | 10/20 | 1 | ENSP00000452711.1 |
Frequencies
GnomAD3 genomes AF: 0.00106 AC: 161AN: 152246Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000884 AC: 222AN: 251094Hom.: 0 AF XY: 0.000862 AC XY: 117AN XY: 135694
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GnomAD4 exome AF: 0.00159 AC: 2319AN: 1461650Hom.: 3 Cov.: 31 AF XY: 0.00156 AC XY: 1134AN XY: 727124
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GnomAD4 genome AF: 0.00106 AC: 162AN: 152364Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61AN XY: 74510
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2024 | AP4E1: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2021 | This variant is associated with the following publications: (PMID: 26544806) - |
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 426 of the AP4E1 protein (p.Ile426Leu). This variant is present in population databases (rs148817957, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with AP4E1-related conditions (PMID: 26544806). ClinVar contains an entry for this variant (Variation ID: 432244). 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: "Tolerated"; 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 12, 2017 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Nov 01, 2017 | - - |
AP4E1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 03, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at