15-50941490-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007347.5(AP4E1):c.992C>T(p.Ser331Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,612,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S331S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

AP4E1
NM_007347.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.77

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

AP-4 deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 51
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
AP4-related intellectual disability and spastic paraplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP4E1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053813636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5 link	c.992C>T	p.Ser331Leu	missense_variant	Exon 9 of 21	ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AP4E1	ENST00000261842.10 link	c.992C>T	p.Ser331Leu	missense_variant	Exon 9 of 21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1 link	c.767C>T	p.Ser256Leu	missense_variant	Exon 9 of 21	1		ENSP00000452976.1
AP4E1	ENST00000558439.5 link	n.*114C>T		non_coding_transcript_exon_variant	Exon 9 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5 link	n.*36C>T		non_coding_transcript_exon_variant	Exon 8 of 20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5 link	n.*114C>T		3_prime_UTR_variant	Exon 9 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5 link	n.*36C>T		3_prime_UTR_variant	Exon 8 of 20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000879

AC:

AN:

250320

AF XY:

0.0000517

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460588

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.000201

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26110

East Asian (EAS)

AF:

0.000278

AC:

AN:

39594

South Asian (SAS)

AF:

0.000209

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111342

Other (OTH)

AF:

0.0000332

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Dec 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 331 of the AP4E1 protein (p.Ser331Leu). This variant is present in population databases (rs199740395, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with AP4E1-related conditions. ClinVar contains an entry for this variant (Variation ID: 445668). 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: "Benign"; 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. -

Inborn genetic diseases

Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.992C>T (p.S331L) alteration is located in exon 9 (coding exon 9) of the AP4E1 gene. This alteration results from a C to T substitution at nucleotide position 992, causing the serine (S) at amino acid position 331 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 07, 2017

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.0065

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.4

L;.

PhyloP100

5.8

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

D;D

REVEL

Benign

0.16

Sift

Benign

0.048

D;T

Sift4G

Uncertain

0.055

T;T

Polyphen

0.89

P;.

Vest4

0.39

MutPred

0.57

Loss of disorder (P = 0.0194);.;

MVP

0.17

MPC

0.13

ClinPred

0.11

GERP RS

5.7

Varity_R

0.44

gMVP

0.33

Mutation Taster

=76/24

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over