Variant 15-50908843-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_007347.5(AP4E1):c.65G>A(p.Gly22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,456,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AP4E1
NM_007347.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.197

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]

AP4E1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000124 (18/1456282) while in subpopulation EAS AF= 0.000405 (16/39520). AF 95% confidence interval is 0.000254. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
AP4E1	NM_007347.5 linkuse as main transcript	c.65G>A	p.Gly22Asp	missense_variant	1/21	ENST00000261842.10	NP_031373.2
AP4E1	NM_001252127.2 linkuse as main transcript	c.-184G>A		5_prime_UTR_variant	1/21		NP_001239056.1
AP4E1	XM_005254264.5 linkuse as main transcript	c.-76+200G>A		intron_variant			XP_005254321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10 linkuse as main transcript	c.65G>A	p.Gly22Asp	missense_variant	1/21	1	NM_007347.5	ENSP00000261842	P1	Q9UPM8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

231566

Hom.:

AF XY:

0.0000393

AC XY:

AN XY:

127250

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000689

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1456282

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

724086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000405

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.65G>A (p.G22D) alteration is located in exon 1 (coding exon 1) of the AP4E1 gene. This alteration results from a G to A substitution at nucleotide position 65, causing the glycine (G) at amino acid position 22 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.065

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.70

M_CAP

Benign

0.012

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

MutationTaster

Benign

0.93

D;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

REVEL

Benign

0.047

Sift

Uncertain

0.014

Sift4G

Uncertain

0.0050

Polyphen

0.0010

Vest4

0.28

MutPred

0.24

Gain of solvent accessibility (P = 0.0638);

MVP

0.18

MPC

0.17

ClinPred

0.088

GERP RS

-8.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over