rs78870657

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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 -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 VariationId is 390912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	NM_007347.5	MANE Select	c.1566C>G	p.Ser522Ser	synonymous	Exon 14 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.1341C>G	p.Ser447Ser	synonymous	Exon 14 of 21	NP_001239056.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.1566C>G	p.Ser522Ser	synonymous	Exon 14 of 21	ENSP00000261842.5
	AP4E1	ENST00000560508.1	TSL:1	c.1341C>G	p.Ser447Ser	synonymous	Exon 14 of 21	ENSP00000452976.1
	AP4E1	ENST00000558439.5	TSL:1	n.*690C>G		non_coding_transcript_exon	Exon 14 of 21	ENSP00000452712.1

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

GnomAD2 exomes AF: 0.000548 AC: 136 AN: 248084 AF XY: 0.000514

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33426

American (AMR) AF: 0.000224 AC: 10 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.000708 AC: 61 AN: 86104

European-Finnish (FIN) AF: 0.00115 AC: 61 AN: 53240

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000652 AC: 724 AN: 1110948

Other (OTH) AF: 0.000498 AC: 30 AN: 60284

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

African (AFR) AF: 0.000120 AC: 5 AN: 41530

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68006

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000508 Hom.: 0

Bravo AF: 0.000419

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.2
DANN	Benign	0.61
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

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: rs78870657; hg19: chr15-51250706;