rs145851652

chr15-50948011-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_007347.5(AP4E1):c.1177-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,582,122 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (24 hom.)
• Consequence: AP4E1 NM_007347.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002387
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.647

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 15-50948011-T-C is Benign according to our data. Variant chr15-50948011-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 210198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-50948011-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00341 (520/152346) while in subpopulation SAS AF= 0.00621 (30/4830). AF 95% confidence interval is 0.00481. There are 0 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP4E1	NM_007347.5	c.1177-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000261842.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP4E1	ENST00000261842.10	c.1177-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_007347.5	P1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00380 AC: 938 AN: 246540 Hom.: 4 AF XY: 0.00400 AC XY: 536 AN XY: 133982

Gnomad AFR exome AF: 0.000782

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00558

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00422 AC: 6035 AN: 1429776 Hom.: 24 Cov.: 29 AF XY: 0.00438 AC XY: 3124 AN XY: 713186

Gnomad4 AFR exome AF: 0.000643

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00154

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.00594

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00362

GnomAD4 genome AF: 0.00341 AC: 520 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74506

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00448 Hom.: 1

Bravo AF: 0.00306

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.00453

EpiControl AF: 0.00363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2015	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2019	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Stuttering, familial persistent, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Hereditary spastic paraplegia 51 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs145851652; hg19: chr15-51240208;