NM_007347.5:c.1694C>T

Variant names:

• chr15-50958637-C-T
• rs142762839
• NM_007347.5:c.1694C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_007347.5(AP4E1):​c.1694C>T​(p.Ala565Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. A565E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: AP4E1 NM_007347.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.57
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019931495).
• BP6: Variant 15-50958637-C-T is Benign according to our data. Variant chr15-50958637-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 568340.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000222 (324/1461838) while in subpopulation EAS AF = 0.000907 (36/39682). AF 95% confidence interval is 0.000673. There are 1 homozygotes in GnomAdExome4. There are 175 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. 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.1694C>T	p.Ala565Val	missense	Exon 14 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.1469C>T	p.Ala490Val	missense	Exon 14 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.1694C>T	p.Ala565Val	missense	Exon 14 of 21	ENSP00000261842.5	Q9UPM8-1
	AP4E1	ENST00000560508.1	TSL:1	c.1469C>T	p.Ala490Val	missense	Exon 14 of 21	ENSP00000452976.1	Q9UPM8-2
	AP4E1	ENST00000558439.5	TSL:1	n.*818C>T		non_coding_transcript_exon	Exon 14 of 21	ENSP00000452712.1	H0YK95

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251322 AF XY: 0.000243

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461838 Hom.: 1 Cov.: 31 AF XY: 0.000241 AC XY: 175 AN XY: 727220

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000907 AC: 36 AN: 39682

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000202 AC: 225 AN: 1111988

Other (OTH) AF: 0.000414 AC: 25 AN: 60392

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152294 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74470

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000248 Hom.: 0

Bravo AF: 0.000178

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Neurodevelopmental delay (1)
-	-	1	not provided (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.059
Sift	Benign	0.072	T
Sift4G	Benign	0.12	T
Polyphen		0.45	B
Vest4		0.10
MutPred		0.52		Gain of helix (P = 0.0425)
MVP		0.21
MPC		0.11
ClinPred		0.029	T
GERP RS		4.2
Varity_R		0.15
gMVP		0.089
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142762839; hg19: chr15-51250834; COSMIC: COSV108032179;