Genetic Variant AP4E1:c.*1548T>C (chr15-51004210-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007347.5(AP4E1):c.*1548T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 151,946 control chromosomes in the GnomAD database, including 27,435 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 27416 hom., cov: 31)

Exomes 𝑓: 0.85 ( 19 hom. )

Consequence

AP4E1
NM_007347.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.44

Publications

11 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5 link	c.*1548T>C		3_prime_UTR_variant	Exon 21 of 21	ENST00000261842.10	NP_031373.2	Q9UPM8-1B4DM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10 link	c.*1548T>C		3_prime_UTR_variant	Exon 21 of 21	1	NM_007347.5	ENSP00000261842.5		Q9UPM8-1
AP4E1	ENST00000560508.1 link	c.*1548T>C		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000452976.1		Q9UPM8-2

Frequencies

GnomAD3 genomes

AF:

0.599

AC:

90898

AN:

151776

Hom.:

27370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.583

Gnomad AMR

AF:

0.474

Gnomad ASJ

AF:

0.616

Gnomad EAS

AF:

0.586

Gnomad SAS

AF:

0.530

Gnomad FIN

AF:

0.572

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.594

GnomAD4 exome

AF:

0.846

AC:

AN:

Hom.:

Cov.:

AF XY:

0.875

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.933

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.722

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.583

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.599

AC:

91004

AN:

151894

Hom.:

27416

Cov.:

AF XY:

0.594

AC XY:

44056

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.621

AC:

25725

AN:

41414

American (AMR)

AF:

0.474

AC:

7233

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.616

AC:

2136

AN:

3468

East Asian (EAS)

AF:

0.586

AC:

3022

AN:

5156

South Asian (SAS)

AF:

0.533

AC:

2567

AN:

4818

European-Finnish (FIN)

AF:

0.572

AC:

6018

AN:

10526

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.623

AC:

42357

AN:

67954

Other (OTH)

AF:

0.592

AC:

1245

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1852

3704

5556

7408

9260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.605

Hom.:

46705

Bravo

AF:

0.588

Asia WGS

AF:

0.559

AC:

1942

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.98

(source)

DANN

Benign

0.73

PhyloP100

-2.4

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over