15-50908846-G-T

Position:

• chr15-50908846-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001252127.2(AP4E1):​c.-181G>T 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 0.000000687 in 1,456,152 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: 34)
  • Exomes 𝑓: 6.9e-7 (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: 2.27

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24416995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.68G>T	p.Gly23Val	missense_variant	1/21	ENST00000261842.10	NP_031373.2
AP4E1	NM_001252127.2	c.-181G>T		5_prime_UTR_premature_start_codon_gain_variant	1/21		NP_001239056.1
AP4E1	NM_001252127.2	c.-181G>T		5_prime_UTR_variant	1/21		NP_001239056.1
AP4E1	XM_005254264.5	c.-76+203G>T		intron_variant			XP_005254321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000560508	c.-181G>T		5_prime_UTR_premature_start_codon_gain_variant	1/21	1		ENSP00000452976.1
AP4E1	ENST00000261842.10	c.68G>T	p.Gly23Val	missense_variant	1/21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508	c.-181G>T		5_prime_UTR_variant	1/21	1		ENSP00000452976.1
AP4E1	ENST00000561393.5	n.-181G>T		5_prime_UTR_premature_start_codon_gain_variant	1/20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.68G>T		non_coding_transcript_exon_variant	1/21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.-181G>T		non_coding_transcript_exon_variant	1/20	1		ENSP00000452711.1
AP4E1	ENST00000561393.5	n.-181G>T		5_prime_UTR_variant	1/20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456152 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2022

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. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with AP4E1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the AP4E1 protein (p.Gly23Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.0014
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.035
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.039	D
Polyphen		0.79	P
Vest4		0.39
MutPred		0.32		Loss of disorder (P = 0.0276);
MVP		0.14
MPC		0.33
ClinPred		0.90	D
GERP RS		5.4
Varity_R		0.25
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-51201043;