rs142762839

chr15-50958637-C-Achr15-50958637-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_007347.5(AP4E1):c.1694C>A(p.Ala565Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A565V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: AP4E1 NM_007347.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.57

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067723393).
• BP6: Variant 15-50958637-C-A is Benign according to our data. Variant chr15-50958637-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434234.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000742 (113/152294) while in subpopulation AFR AF= 0.00257 (107/41556). AF 95% confidence interval is 0.00218. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4E1	NM_007347.5	c.1694C>A	p.Ala565Glu	missense_variant	14/21	ENST00000261842.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4E1	ENST00000261842.10	c.1694C>A	p.Ala565Glu	missense_variant	14/21	1	NM_007347.5	P1
AP4E1	ENST00000560508.1	c.1469C>A	p.Ala490Glu	missense_variant	14/21	1
AP4E1	ENST00000558439.5	c.*818C>A		3_prime_UTR_variant, NMD_transcript_variant	14/21	1
AP4E1	ENST00000561393.5	c.*738C>A		3_prime_UTR_variant, NMD_transcript_variant	13/20	1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251322 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135824

Gnomad AFR exome AF: 0.00252

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: 0.000163

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727220

Gnomad4 AFR exome AF: 0.00245

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152294 Hom.: 0 Cov.: 31 AF XY: 0.000671 AC XY: 50 AN XY: 74470

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000865

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 01, 2016

- -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.11
Sift	Benign	0.37	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.47	P;.
Vest4		0.35
MVP		0.30
MPC		0.13
ClinPred		0.045	T
GERP RS		4.2
Varity_R		0.19
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs142762839; hg19: chr15-51250834;