rs1147129

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007347.5(AP4E1):c.222+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,603,050 control chromosomes in the GnomAD database, including 245,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24500 hom., cov: 33)

Exomes 𝑓: 0.55 ( 221047 hom. )

Consequence

AP4E1
NM_007347.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.00700

Publications

16 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 15-50912167-G-A is Benign according to our data. Variant chr15-50912167-G-A is described in ClinVar as [Benign]. Clinvar id is 380768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5 link	c.222+18G>A		intron_variant	Intron 2 of 20	ENST00000261842.10	NP_031373.2	Q9UPM8-1B4DM48

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP4E1	ENST00000261842.10 link	c.222+18G>A	intron_variant	Intron 2 of 20	1	NM_007347.5	ENSP00000261842.5	Q9UPM8-1
AP4E1	ENST00000560508.1 link	c.-27+18G>A	intron_variant	Intron 2 of 20	1		ENSP00000452976.1	Q9UPM8-2
AP4E1	ENST00000558439.5 link	n.222+18G>A	intron_variant	Intron 2 of 20	1		ENSP00000452712.1	H0YK95
AP4E1	ENST00000561393.5 link	n.-27+18G>A	intron_variant	Intron 2 of 19	1		ENSP00000452711.1	H0YK94

Frequencies

GnomAD3 genomes

AF:

0.566

AC:

85913

AN:

151904

Hom.:

24490

Cov.:

show subpopulations

Gnomad AFR

AF:

0.606

Gnomad AMI

AF:

0.479

Gnomad AMR

AF:

0.613

Gnomad ASJ

AF:

0.654

Gnomad EAS

AF:

0.414

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.533

Gnomad OTH

AF:

0.568

GnomAD2 exomes

AF:

0.570

AC:

143375

AN:

251352

AF XY:

0.569

show subpopulations

Gnomad AFR exome

AF:

0.602

Gnomad AMR exome

AF:

0.672

Gnomad ASJ exome

AF:

0.649

Gnomad EAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.573

Gnomad NFE exome

AF:

0.540

Gnomad OTH exome

AF:

0.569

GnomAD4 exome

AF:

0.549

AC:

796634

AN:

1451028

Hom.:

221047

Cov.:

AF XY:

0.550

AC XY:

397446

AN XY:

722558

show subpopulations

African (AFR)

AF:

0.614

AC:

20441

AN:

33276

American (AMR)

AF:

0.663

AC:

29660

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.657

AC:

17127

AN:

26072

East Asian (EAS)

AF:

0.424

AC:

16782

AN:

39614

South Asian (SAS)

AF:

0.611

AC:

52568

AN:

86006

European-Finnish (FIN)

AF:

0.566

AC:

30245

AN:

53406

Middle Eastern (MID)

AF:

0.637

AC:

3666

AN:

5752

European-Non Finnish (NFE)

AF:

0.538

AC:

592965

AN:

1102164

Other (OTH)

AF:

0.553

AC:

33180

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

17385

34770

52154

69539

86924

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.565

AC:

85962

AN:

152022

Hom.:

24500

Cov.:

AF XY:

0.568

AC XY:

42182

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.606

AC:

25144

AN:

41478

American (AMR)

AF:

0.612

AC:

9349

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

2268

AN:

3470

East Asian (EAS)

AF:

0.413

AC:

2134

AN:

5162

South Asian (SAS)

AF:

0.616

AC:

2971

AN:

4820

European-Finnish (FIN)

AF:

0.577

AC:

6080

AN:

10546

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.533

AC:

36201

AN:

67964

Other (OTH)

AF:

0.569

AC:

1201

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1929

3859

5788

7718

9647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.554

Hom.:

8205

Bravo

AF:

0.571

Asia WGS

AF:

0.521

AC:

1814

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 51

Benign:3

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 01, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

0.0070

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs1147129

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