chr15-50950080-T-C

Variant names:

• chr15-50950080-T-C
• rs766895434
• NM_007347.5:c.1459T>C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_007347.5(AP4E1):​c.1459T>C​(p.Leu487Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: AP4E1 NM_007347.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.483

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 15-50950080-T-C is Benign according to our data. Variant chr15-50950080-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 434238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.483 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000657 (10/152252) while in subpopulation AMR AF= 0.000523 (8/15292). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4E1	NM_007347.5	c.1459T>C	p.Leu487Leu	synonymous_variant	Exon 13 of 21	ENST00000261842.10	NP_031373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4E1	ENST00000261842.10	c.1459T>C	p.Leu487Leu	synonymous_variant	Exon 13 of 21	1	NM_007347.5	ENSP00000261842.5
AP4E1	ENST00000560508.1	c.1234T>C	p.Leu412Leu	synonymous_variant	Exon 13 of 21	1		ENSP00000452976.1
AP4E1	ENST00000558439.5	n.*583T>C		non_coding_transcript_exon_variant	Exon 13 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*503T>C		non_coding_transcript_exon_variant	Exon 12 of 20	1		ENSP00000452711.1
AP4E1	ENST00000558439.5	n.*583T>C		3_prime_UTR_variant	Exon 13 of 21	1		ENSP00000452712.1
AP4E1	ENST00000561393.5	n.*503T>C		3_prime_UTR_variant	Exon 12 of 20	1		ENSP00000452711.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000199 AC: 5 AN: 250980 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000882

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460796 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000523

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: 0.0000450 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 27, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.82

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: rs766895434; hg19: chr15-51242277;