NM_007347.5:c.1566C>G

Variant names:

• chr15-50958509-C-G
• rs78870657
• NM_007347.5:c.1566C>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_007347.5(AP4E1):​c.1566C>G​(p.Ser522Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,612,216 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: AP4E1 NM_007347.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.133

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 15-50958509-C-G is Benign according to our data. Variant chr15-50958509-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 390912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-50958509-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.133 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000394 (60/152224) while in subpopulation SAS AF= 0.000829 (4/4828). AF 95% confidence interval is 0.000405. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.1566C>G	p.Ser522Ser	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.1566C>G	p.Ser522Ser	synonymous_variant	Exon 14 of 21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.1341C>G	p.Ser447Ser	synonymous_variant	Exon 14 of 21	1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.*690C>G		non_coding_transcript_exon_variant	Exon 14 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*610C>G		non_coding_transcript_exon_variant	Exon 13 of 20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.*690C>G		3_prime_UTR_variant	Exon 14 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*610C>G		3_prime_UTR_variant	Exon 13 of 20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000548 AC: 136 AN: 248084 Hom.: 0 AF XY: 0.000514 AC XY: 69 AN XY: 134146

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000657

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.000779

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000610 AC: 890 AN: 1459992 Hom.: 2 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 726250

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000708

Gnomad4 FIN exome AF: 0.00115

Gnomad4 NFE exome AF: 0.000652

Gnomad4 OTH exome AF: 0.000498

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152224 Hom.: 0 Cov.: 31 AF XY: 0.000323 AC XY: 24 AN XY: 74418

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 15, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic paraplegia Benign:1

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP4E1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.61

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: rs78870657; hg19: chr15-51250706;