rs1555462184

Variant names:

• chr15-50993510-C-CTA
• rs1555462184
• NM_007347.5:c.2234_2235dupTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007347.5(AP4E1):​c.2234_2235dupTA​(p.Thr746fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP4E1 NM_007347.5 frameshift, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.187
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-50993510-C-CTA is Pathogenic according to our data. Variant chr15-50993510-C-CTA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 548459.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007347.5. 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.2234_2235dupTA	p.Thr746fs	frameshift stop_gained	Exon 17 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.2009_2010dupTA	p.Thr671fs	frameshift stop_gained	Exon 17 of 21	NP_001239056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.2234_2235dupTA	p.Thr746fs	frameshift stop_gained	Exon 17 of 21	ENSP00000261842.5
	AP4E1	ENST00000560508.1	TSL:1	c.2009_2010dupTA	p.Thr671fs	frameshift stop_gained	Exon 17 of 21	ENSP00000452976.1
	AP4E1	ENST00000558439.5	TSL:1	n.*1358_*1359dupTA		non_coding_transcript_exon	Exon 17 of 21	ENSP00000452712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Stuttering, familial persistent, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19

Splicing

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

Other links and lift over

dbSNP: rs1555462184; hg19: chr15-51285707;