rs759539551

Variant names:

• chr15-50958758-C-T
• rs759539551
• NM_007347.5:c.1815C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_007347.5(AP4E1):​c.1815C>T​(p.Ser605Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,614,002 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000068 (1 hom.)
• Consequence: AP4E1 NM_007347.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.267

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-50958758-C-T is Benign according to our data. Variant chr15-50958758-C-T is described in ClinVar as [Benign]. Clinvar id is 458247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.267 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000112 (17/152180) while in subpopulation AMR AF= 0.000982 (15/15280). AF 95% confidence interval is 0.000605. There are 1 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.1815C>T	p.Ser605Ser	synonymous_variant	Exon 14 of 21	ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.1815C>T	p.Ser605Ser	synonymous_variant	Exon 14 of 21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.1590C>T	p.Ser530Ser	synonymous_variant	Exon 14 of 21	1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.*939C>T		non_coding_transcript_exon_variant	Exon 14 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*859C>T		non_coding_transcript_exon_variant	Exon 13 of 20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.*939C>T		3_prime_UTR_variant	Exon 14 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*859C>T		3_prime_UTR_variant	Exon 13 of 20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152180 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000347 AC: 87 AN: 251076 Hom.: 1 AF XY: 0.000251 AC XY: 34 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 100 AN: 1461822 Hom.: 1 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152180 Hom.: 1 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000189

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AP4E1-related disorder Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.8
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs759539551; hg19: chr15-51250955;