rs1147129

Variant names:

• chr15-50912167-G-A
• rs1147129
• NM_007347.5:c.222+18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007347.5(AP4E1):​c.222+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,603,050 control chromosomes in the GnomAD database, including 245,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24500 hom., cov: 33)
  • Exomes 𝑓: 0.55 (221047 hom.)
• Consequence: AP4E1 NM_007347.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00700
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-50912167-G-A is Benign according to our data. Variant chr15-50912167-G-A is described in ClinVar as Benign. ClinVar VariationId is 380768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

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.222+18G>A		intron	N/A	NP_031373.2
	AP4E1	NM_001252127.2		c.-27+18G>A		intron	N/A	NP_001239056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.222+18G>A		intron	N/A	ENSP00000261842.5
	AP4E1	ENST00000560508.1	TSL:1	c.-27+18G>A		intron	N/A	ENSP00000452976.1
	AP4E1	ENST00000558439.5	TSL:1	n.222+18G>A		intron	N/A	ENSP00000452712.1

Frequencies

GnomAD3 genomes AF: 0.566 AC: 85913 AN: 151904 Hom.: 24490 Cov.: 33

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.479

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.568

GnomAD2 exomes AF: 0.570 AC: 143375 AN: 251352 AF XY: 0.569

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.672

Gnomad ASJ exome AF: 0.649

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.573

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.549 AC: 796634 AN: 1451028 Hom.: 221047 Cov.: 31 AF XY: 0.550 AC XY: 397446 AN XY: 722558

African (AFR) AF: 0.614 AC: 20441 AN: 33276

American (AMR) AF: 0.663 AC: 29660 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 17127 AN: 26072

East Asian (EAS) AF: 0.424 AC: 16782 AN: 39614

South Asian (SAS) AF: 0.611 AC: 52568 AN: 86006

European-Finnish (FIN) AF: 0.566 AC: 30245 AN: 53406

Middle Eastern (MID) AF: 0.637 AC: 3666 AN: 5752

European-Non Finnish (NFE) AF: 0.538 AC: 592965 AN: 1102164

Other (OTH) AF: 0.553 AC: 33180 AN: 60032

GnomAD4 genome AF: 0.565 AC: 85962 AN: 152022 Hom.: 24500 Cov.: 33 AF XY: 0.568 AC XY: 42182 AN XY: 74302

African (AFR) AF: 0.606 AC: 25144 AN: 41478

American (AMR) AF: 0.612 AC: 9349 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2268 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2134 AN: 5162

South Asian (SAS) AF: 0.616 AC: 2971 AN: 4820

European-Finnish (FIN) AF: 0.577 AC: 6080 AN: 10546

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36201 AN: 67964

Other (OTH) AF: 0.569 AC: 1201 AN: 2112

Alfa AF: 0.554 Hom.: 8205

Bravo AF: 0.571

Asia WGS AF: 0.521 AC: 1814 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary spastic paraplegia 51 (3)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.0070
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: rs1147129; hg19: chr15-51204364; COSMIC: COSV55917175; COSMIC: COSV55917175;