rs4775912

Variant names:

• chr15-50988782-T-C
• rs4775912
• NM_007347.5:c.2091-4588T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007347.5(AP4E1):​c.2091-4588T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 152,118 control chromosomes in the GnomAD database, including 2,809 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2809 hom., cov: 32)
• Consequence: AP4E1 NM_007347.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.561
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.2091-4588T>C		intron_variant	Intron 16 of 20	ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.2091-4588T>C		intron_variant	Intron 16 of 20	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.1866-4588T>C		intron_variant	Intron 16 of 20	1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.*1215-4588T>C		intron_variant	Intron 16 of 20	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*1135-4588T>C		intron_variant	Intron 15 of 19	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27659 AN: 152000 Hom.: 2809 Cov.: 32

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.206

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.182 AC: 27665 AN: 152118 Hom.: 2809 Cov.: 32 AF XY: 0.182 AC XY: 13537 AN XY: 74360

African (AFR) AF: 0.213 AC: 8837 AN: 41478

American (AMR) AF: 0.275 AC: 4204 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3468

East Asian (EAS) AF: 0.0177 AC: 92 AN: 5184

South Asian (SAS) AF: 0.197 AC: 948 AN: 4820

European-Finnish (FIN) AF: 0.121 AC: 1283 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10842 AN: 67994

Other (OTH) AF: 0.203 AC: 429 AN: 2110

Alfa AF: 0.178 Hom.: 4500

Bravo AF: 0.196

Asia WGS AF: 0.102 AC: 353 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.24
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4775912; hg19: chr15-51280979;