ENST00000560508.1:c.-52C>T

Variant names:

• chr15-50912124-C-T
• rs1555453222
• ENST00000560508.1:c.-52C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000560508.1(AP4E1):​c.-52C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: AP4E1 ENST00000560508.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

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]

AP4E1 Gene-Disease associations (from GenCC):

• AP-4 deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 51

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1443057).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000560508.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	NM_007347.5	MANE Select	c.197C>T	p.Thr66Ile	missense	Exon 2 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.-52C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_001239056.1
	AP4E1	NM_001252127.2		c.-52C>T		5_prime_UTR	Exon 2 of 21	NP_001239056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000560508.1	TSL:1	c.-52C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000452976.1
	AP4E1	ENST00000561393.5	TSL:1	n.-52C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 20	ENSP00000452711.1
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.197C>T	p.Thr66Ile	missense	Exon 2 of 21	ENSP00000261842.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.078
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.039
Sift	Benign	0.13	T
Sift4G	Benign	0.069	T
Polyphen		0.12	B
Vest4		0.42
MutPred		0.44		Loss of disorder (P = 0.0182)
MVP		0.19
MPC		0.26
ClinPred		0.69	D
GERP RS		5.2
Varity_R		0.18
gMVP		0.20

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

Other links and lift over

dbSNP: rs1555453222; hg19: chr15-51204321;