15-50908741-G-GATCGCGGGCGGCGGCGGC

Position:

• chr15-50908741-G-GATCGCGGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_007347.5(AP4E1):​c.-19_-2dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00384 in 152,094 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: AP4E1 NM_007347.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.47

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 -6 ACMG points.

• BP6: Variant 15-50908741-G-GATCGCGGGCGGCGGCGGC is Benign according to our data. Variant chr15-50908741-G-GATCGCGGGCGGCGGCGGC is described in ClinVar as [Likely_benign]. Clinvar id is 506560.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00384 (584/152094) while in subpopulation SAS AF= 0.00644 (31/4814). AF 95% confidence interval is 0.00507. There are 1 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.-19_-2dup		5_prime_UTR_variant	1/21	ENST00000261842.10	NP_031373.2
AP4E1	NM_001252127.2	c.-267_-250dup		5_prime_UTR_variant	1/21		NP_001239056.1
AP4E1	XM_005254264.5	c.-76+117_-76+134dup		intron_variant			XP_005254321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.-19_-2dup		5_prime_UTR_variant	1/21	1	NM_007347.5	ENSP00000261842	P1
AP4E1	ENST00000558439.5	c.-19_-2dup		5_prime_UTR_variant, NMD_transcript_variant	1/21	1		ENSP00000452712
AP4E1	ENST00000561393.5	c.-267_-250dup		5_prime_UTR_variant, NMD_transcript_variant	1/20	1		ENSP00000452711
AP4E1	ENST00000561441.5	c.-19_-2dup		5_prime_UTR_variant, NMD_transcript_variant	1/13	2		ENSP00000453112

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 586 AN: 151980 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00555

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00103 AC: 107 AN: 103648 Hom.: 0 AF XY: 0.00107 AC XY: 62 AN XY: 58028

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.000527

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.000710

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00398 AC: 5364 AN: 1346484 Hom.: 15 Cov.: 30 AF XY: 0.00407 AC XY: 2704 AN XY: 663908

Gnomad4 AFR exome AF: 0.00203

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00125

Gnomad4 EAS exome AF: 0.000229

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.000803

Gnomad4 NFE exome AF: 0.00451

Gnomad4 OTH exome AF: 0.00319

GnomAD4 genome AF: 0.00384 AC: 584 AN: 152094 Hom.: 1 Cov.: 33 AF XY: 0.00389 AC XY: 289 AN XY: 74368

Gnomad4 AFR AF: 0.00174

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00644

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00553

Gnomad4 OTH AF: 0.00522

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2017

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. -

AP4E1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745897561; hg19: chr15-51200938;