Variant 15-50958618-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007347.5(AP4E1):c.1675A>C(p.Thr559Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AP4E1
NM_007347.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.46

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 Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5 linkuse as main transcript	c.1675A>C	p.Thr559Pro	missense_variant	14/21	ENST00000261842.10	NP_031373.2	Q9UPM8-1B4DM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP4E1	ENST00000261842.10 linkuse as main transcript	c.1675A>C	p.Thr559Pro	missense_variant	14/21	1	NM_007347.5	ENSP00000261842.5	Q9UPM8-1
AP4E1	ENST00000560508.1 linkuse as main transcript	c.1450A>C	p.Thr484Pro	missense_variant	14/21	1		ENSP00000452976.1	Q9UPM8-2
AP4E1	ENST00000558439.5 linkuse as main transcript	n.*799A>C		non_coding_transcript_exon_variant	14/21	1		ENSP00000452712.1	H0YK95
AP4E1	ENST00000561393.5 linkuse as main transcript	n.*719A>C		non_coding_transcript_exon_variant	13/20	1		ENSP00000452711.1	H0YK94
AP4E1	ENST00000558439.5 linkuse as main transcript	n.*799A>C		3_prime_UTR_variant	14/21	1		ENSP00000452712.1	H0YK95
AP4E1	ENST00000561393.5 linkuse as main transcript	n.*719A>C		3_prime_UTR_variant	13/20	1		ENSP00000452711.1	H0YK94

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135828

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 20, 2016

- -

Hereditary spastic paraplegia 51;C3489627:Stuttering, familial persistent, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.016

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.023

D;D

Sift4G

Benign

0.075

T;T

Polyphen

1.0

D;.

Vest4

0.69

MutPred

0.80

Gain of methylation at K560 (P = 0.0904);.;

MVP

0.32

MPC

0.54

ClinPred

0.96

GERP RS

4.2

Varity_R

0.84

gMVP

0.63

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