15-50908845-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_007347.5(AP4E1):ā€‹c.67G>Cā€‹(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,608,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 34)
Exomes š‘“: 0.000030 ( 0 hom. )

Consequence

AP4E1
NM_007347.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.85
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24289638).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AP4E1NM_007347.5 linkuse as main transcriptc.67G>C p.Gly23Arg missense_variant 1/21 ENST00000261842.10 NP_031373.2
AP4E1NM_001252127.2 linkuse as main transcriptc.-182G>C 5_prime_UTR_variant 1/21 NP_001239056.1
AP4E1XM_005254264.5 linkuse as main transcriptc.-76+202G>C intron_variant XP_005254321.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AP4E1ENST00000261842.10 linkuse as main transcriptc.67G>C p.Gly23Arg missense_variant 1/211 NM_007347.5 ENSP00000261842 P1Q9UPM8-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152232
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000866
AC:
2
AN:
230970
Hom.:
0
AF XY:
0.00000787
AC XY:
1
AN XY:
127064
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000198
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000302
AC:
44
AN:
1456356
Hom.:
0
Cov.:
31
AF XY:
0.0000221
AC XY:
16
AN XY:
724134
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000396
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152232
Hom.:
0
Cov.:
34
AF XY:
0.0000403
AC XY:
3
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000189
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000832
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 06, 2020In 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. 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"). This variant has not been reported in the literature in individuals with AP4E1-related conditions. This variant is present in population databases (rs373684336, ExAC 0.003%). This sequence change replaces glycine with arginine at codon 23 of the AP4E1 protein (p.Gly23Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.058
T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.24
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.81
L
MutationTaster
Benign
0.67
D;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.2
N
REVEL
Benign
0.038
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.017
D
Polyphen
0.88
P
Vest4
0.42
MVP
0.17
MPC
0.41
ClinPred
0.74
D
GERP RS
1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.12
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373684336; hg19: chr15-51201042; API