15-50908843-G-A

Position:

• chr15-50908843-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_001252127.2(AP4E1):​c.-184G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,456,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AP4E1 NM_001252127.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.197

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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000124 (18/1456282) while in subpopulation EAS AF= 0.000405 (16/39520). AF 95% confidence interval is 0.000254. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.65G>A	p.Gly22Asp	missense_variant	1/21	ENST00000261842.10	NP_031373.2
AP4E1	NM_001252127.2	c.-184G>A		5_prime_UTR_premature_start_codon_gain_variant	1/21		NP_001239056.1
AP4E1	NM_001252127.2	c.-184G>A		5_prime_UTR_variant	1/21		NP_001239056.1
AP4E1	XM_005254264.5	c.-76+200G>A		intron_variant			XP_005254321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000560508	c.-184G>A		5_prime_UTR_premature_start_codon_gain_variant	1/21	1		ENSP00000452976.1
AP4E1	ENST00000261842.10	c.65G>A	p.Gly22Asp	missense_variant	1/21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508	c.-184G>A		5_prime_UTR_variant	1/21	1		ENSP00000452976.1
AP4E1	ENST00000561393.5	n.-184G>A		5_prime_UTR_premature_start_codon_gain_variant	1/20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.65G>A		non_coding_transcript_exon_variant	1/21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.-184G>A		non_coding_transcript_exon_variant	1/20	1		ENSP00000452711.1
AP4E1	ENST00000561393.5	n.-184G>A		5_prime_UTR_variant	1/20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000518 AC: 12 AN: 231566 Hom.: 0 AF XY: 0.0000393 AC XY: 5 AN XY: 127250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000689

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1456282 Hom.: 0 Cov.: 31 AF XY: 0.00000829 AC XY: 6 AN XY: 724086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000405

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.65G>A (p.G22D) alteration is located in exon 1 (coding exon 1) of the AP4E1 gene. This alteration results from a G to A substitution at nucleotide position 65, causing the glycine (G) at amino acid position 22 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.065	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.047
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.24		Gain of solvent accessibility (P = 0.0638);
MVP		0.18
MPC		0.17
ClinPred		0.088	T
GERP RS		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs766330413; hg19: chr15-51201040;