rs142215198

Variant names:

• chr15-50968263-G-A
• rs142215198
• NM_007347.5:c.1852G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS1

The NM_007347.5(AP4E1):​c.1852G>A​(p.Val618Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000347 in 1,606,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V618G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: AP4E1 NM_007347.5 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: 8.34
• Publications: 5 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 15-50968263-G-A is Benign according to our data. Variant chr15-50968263-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 240837.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000335 (51/152034) while in subpopulation NFE AF = 0.000603 (41/67970). AF 95% confidence interval is 0.000457. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1852G>A	p.Val618Ile	missense splice_region	Exon 15 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.1627G>A	p.Val543Ile	missense splice_region	Exon 15 of 21	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.1852G>A	p.Val618Ile	missense splice_region	Exon 15 of 21	ENSP00000261842.5	Q9UPM8-1
	AP4E1	ENST00000560508.1	TSL:1	c.1627G>A	p.Val543Ile	missense splice_region	Exon 15 of 21	ENSP00000452976.1	Q9UPM8-2
	AP4E1	ENST00000558439.5	TSL:1	n.*976G>A		splice_region non_coding_transcript_exon	Exon 15 of 21	ENSP00000452712.1	H0YK95

Frequencies

GnomAD3 genomes AF: 0.000336 AC: 51 AN: 151916 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000263 AC: 65 AN: 247056 AF XY: 0.000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000348 AC: 506 AN: 1454842 Hom.: 1 Cov.: 29 AF XY: 0.000391 AC XY: 283 AN XY: 723808

African (AFR) AF: 0.0000301 AC: 1 AN: 33230

American (AMR) AF: 0.000314 AC: 14 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26080

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39446

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85748

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53164

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.000405 AC: 448 AN: 1106718

Other (OTH) AF: 0.000449 AC: 27 AN: 60108

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74310

African (AFR) AF: 0.0000723 AC: 3 AN: 41470

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67970

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000321 AC: 39

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	-	Spastic paraplegia (1)
-	-	-	Hereditary spastic paraplegia 51 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.15
Sift	Benign	0.16	T
Sift4G	Uncertain	0.022	D
Polyphen		0.55	P
Vest4		0.45
MVP		0.37
MPC		0.29
ClinPred		0.080	T
GERP RS		4.7
Varity_R		0.079
gMVP		0.21
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.10		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: rs142215198; hg19: chr15-51260460;