rs1147129

Positions:

• chr15-50912167-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00700

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 -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. Variant chr15-50912167-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.222+18G>A		intron_variant		ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.222+18G>A		intron_variant		1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.-27+18G>A		intron_variant		1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.222+18G>A		intron_variant		1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.-27+18G>A		intron_variant		1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85913 AN: 151904 Hom.: 24490 Cov.: 33

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

GnomAD3 exomes AF: 0.570 AC: 143375 AN: 251352 Hom.: 41599 AF XY: 0.569 AC XY: 77298 AN XY: 135870

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 SAS exome AF: 0.609

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.: 31 AF XY: 0.550 AC XY: 397446 AN XY: 722558

Gnomad4 AFR exome AF: 0.614

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.657

Gnomad4 EAS exome AF: 0.424

Gnomad4 SAS exome AF: 0.611

Gnomad4 FIN exome AF: 0.566

Gnomad4 NFE exome AF: 0.538

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.565 AC: 85962 AN: 152022 Hom.: 24500 Cov.: 33 AF XY: 0.568 AC XY: 42182 AN XY: 74302

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.413

Gnomad4 SAS AF: 0.616

Gnomad4 FIN AF: 0.577

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.569

Alfa AF: 0.562 Hom.: 4945

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

Submissions by phenotype

Hereditary spastic paraplegia 51 Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 01, 2016

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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.79

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

Other links and lift over

dbSNP: rs1147129; hg19: chr15-51204364; COSMIC: COSV55917175; COSMIC: COSV55917175;