rs145851652

Variant names:

• chr15-50948011-T-C
• rs145851652
• NM_007347.5:c.1177-9T>C

Variant summary

Our verdict is Benign. The variant received -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 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 intron
• Scores: Splicing: ADA: 0.00002387
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.647
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• AP4-related intellectual disability and spastic paraplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 210198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 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.1177-9T>C		intron	N/A	NP_031373.2
	AP4E1	NM_001252127.2		c.952-9T>C		intron	N/A	NP_001239056.1	Q9UPM8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.1177-9T>C		intron	N/A	ENSP00000261842.5	Q9UPM8-1
	AP4E1	ENST00000560508.1	TSL:1	c.952-9T>C		intron	N/A	ENSP00000452976.1	Q9UPM8-2
	AP4E1	ENST00000558439.5	TSL:1	n.*299-9T>C		intron	N/A	ENSP00000452712.1	H0YK95

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

GnomAD2 exomes AF: 0.00380 AC: 938 AN: 246540 AF XY: 0.00400

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 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

African (AFR) AF: 0.000643 AC: 21 AN: 32678

American (AMR) AF: 0.00242 AC: 108 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 40 AN: 25906

East Asian (EAS) AF: 0.0000762 AC: 3 AN: 39368

South Asian (SAS) AF: 0.00594 AC: 508 AN: 85456

European-Finnish (FIN) AF: 0.00116 AC: 60 AN: 51912

Middle Eastern (MID) AF: 0.00194 AC: 11 AN: 5672

European-Non Finnish (NFE) AF: 0.00467 AC: 5069 AN: 1084840

Other (OTH) AF: 0.00362 AC: 215 AN: 59366

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

African (AFR) AF: 0.000818 AC: 34 AN: 41578

American (AMR) AF: 0.00405 AC: 62 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00526 AC: 358 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 51 (1)
-	-	1	Spastic paraplegia (1)
-	-	1	Stuttering, familial persistent, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.86
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs145851652; hg19: chr15-51240208;