rs142215198

Positions:

• chr15-50968263-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_007347.5(AP4E1):​c.1852G>A​(p.Val618Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,606,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: AP4E1 NM_007347.5 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: 8.34

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 15-50968263-G-A is Benign according to our data. Variant chr15-50968263-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240837.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152034) while in subpopulation NFE AF= 0.000603 (41/67970). AF 95% confidence interval is 0.000457. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.1852G>A	p.Val618Ile	missense_variant, splice_region_variant	15/21	ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.1852G>A	p.Val618Ile	missense_variant, splice_region_variant	15/21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.1627G>A	p.Val543Ile	missense_variant, splice_region_variant	15/21	1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.*976G>A		splice_region_variant, non_coding_transcript_exon_variant	15/21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*896G>A		splice_region_variant, non_coding_transcript_exon_variant	14/20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.*976G>A		3_prime_UTR_variant	15/21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*896G>A		3_prime_UTR_variant	14/20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000263 AC: 65 AN: 247056 Hom.: 1 AF XY: 0.000299 AC XY: 40 AN XY: 133654

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000348 AC: 506 AN: 1454842 Hom.: 1 Cov.: 29 AF XY: 0.000391 AC XY: 283 AN XY: 723808

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000405

Gnomad4 OTH exome AF: 0.000449

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74310

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000321 AC: 39

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	AP4E1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2019	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 01, 2024	BP4 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2022

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 618 of the AP4E1 protein (p.Val618Ile). This variant is present in population databases (rs142215198, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with intellectual disability (PMID: 25167861, 26544806). ClinVar contains an entry for this variant (Variation ID: 240837). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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. -

Hereditary spastic paraplegia 51 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant classified as Uncertain significance and reported on 01-25-2022 by Invitae . Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.55	P;.
Vest4		0.45
MVP		0.37
MPC		0.29
ClinPred		0.080	T
GERP RS		4.7
Varity_R		0.079
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.10		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: rs142215198; hg19: chr15-51260460;