rs115188375

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007347.5(AP4E1):c.2755A>G(p.Met919Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,613,886 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 6 hom. )

Consequence

AP4E1
NM_007347.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.167

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028902292).

BP6

Variant 15-50997734-A-G is Benign according to our data. Variant chr15-50997734-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00463 (705/152328) while in subpopulation AFR AF= 0.0159 (661/41568). AF 95% confidence interval is 0.0149. There are 7 homozygotes in gnomad4. There are 316 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5 link	c.2755A>G	p.Met919Val	missense_variant	Exon 18 of 21	ENST00000261842.10	NP_031373.2	Q9UPM8-1B4DM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP4E1	ENST00000261842.10 link	c.2755A>G	p.Met919Val	missense_variant	Exon 18 of 21	1	NM_007347.5	ENSP00000261842.5	Q9UPM8-1
AP4E1	ENST00000560508.1 link	c.2530A>G	p.Met844Val	missense_variant	Exon 18 of 21	1		ENSP00000452976.1	Q9UPM8-2
AP4E1	ENST00000558439.5 link	n.*1879A>G		non_coding_transcript_exon_variant	Exon 18 of 21	1		ENSP00000452712.1	H0YK95
AP4E1	ENST00000561393.5 link	n.*1799A>G		non_coding_transcript_exon_variant	Exon 17 of 20	1		ENSP00000452711.1	H0YK94
AP4E1	ENST00000558439.5 link	n.*1879A>G		3_prime_UTR_variant	Exon 18 of 21	1		ENSP00000452712.1	H0YK95
AP4E1	ENST00000561393.5 link	n.*1799A>G		3_prime_UTR_variant	Exon 17 of 20	1		ENSP00000452711.1	H0YK94

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

702

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

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:

0.0000147

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00127

AC:

318

AN:

250798

Hom.:

AF XY:

0.000959

AC XY:

130

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.0181

Gnomad AMR exome

AF:

0.000580

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:

0.00000882

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000487

AC:

712

AN:

1461558

Hom.:

Cov.:

AF XY:

0.000395

AC XY:

287

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0182

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.00463

AC:

705

AN:

152328

Hom.:

Cov.:

AF XY:

0.00424

AC XY:

316

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0159

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00425

Alfa

AF:

0.000732

Hom.:

Bravo

AF:

0.00560

ESP6500AA

AF:

0.0143

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00153

AC:

186

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 22, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 25, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Mar 26, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Sep 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stuttering, familial persistent, 1

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AP4E1-related disorder

Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia 51

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.025

DANN

Benign

0.35

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.36

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.27

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

0.020

N;N

REVEL

Benign

0.054

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.060

MVP

0.16

MPC

0.10

ClinPred

0.0019

GERP RS

-1.5

Varity_R

0.048

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

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