15-50908739-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007347.5(AP4E1):c.-40G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00603 in 1,495,632 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 34)
  • Exomes 𝑓: 0.0063 (34 hom.)
• Consequence: AP4E1 NM_007347.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-50908739-G-A is Benign according to our data. Variant chr15-50908739-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 509373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00367 (559/152138) while in subpopulation NFE AF= 0.00699 (475/67974). AF 95% confidence interval is 0.00647. There are 4 homozygotes in gnomad4. There are 246 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4E1	NM_007347.5	c.-40G>A		5_prime_UTR_variant	1/21	ENST00000261842.10
AP4E1	NM_001252127.2	c.-288G>A		5_prime_UTR_variant	1/21
AP4E1	XM_005254264.5	c.-76+96G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4E1	ENST00000261842.10	c.-40G>A		5_prime_UTR_variant	1/21	1	NM_007347.5	P1
AP4E1	ENST00000558439.5	c.-40G>A		5_prime_UTR_variant, NMD_transcript_variant	1/21	1
AP4E1	ENST00000561393.5	c.-288G>A		5_prime_UTR_variant, NMD_transcript_variant	1/20	1
AP4E1	ENST00000561441.5	c.-40G>A		5_prime_UTR_variant, NMD_transcript_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 559 AN: 152024 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00699

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00331 AC: 336 AN: 101638 Hom.: 2 AF XY: 0.00315 AC XY: 179 AN XY: 56858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00122

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000995

Gnomad NFE exome AF: 0.00760

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00629 AC: 8453 AN: 1343494 Hom.: 34 Cov.: 30 AF XY: 0.00596 AC XY: 3944 AN XY: 662238

Gnomad4 AFR exome AF: 0.000741

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.000735

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.00764

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.00367 AC: 559 AN: 152138 Hom.: 4 Cov.: 34 AF XY: 0.00331 AC XY: 246 AN XY: 74382

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00699

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00337 Hom.: 2

Bravo AF: 0.00349

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.9
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs374083032; hg19: chr15-51200936;