rs58909326

Variant names:

• chr15-50941684-A-G
• rs58909326
• NM_007347.5:c.1085A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-50941684-A-G
• chr15-50941684-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007347.5(AP4E1):​c.1085A>G​(p.Tyr362Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0025 in 1,613,614 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: AP4E1 NM_007347.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.92
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053795576).
• BP6: Variant 15-50941684-A-G is Benign according to our data. Variant chr15-50941684-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2040/152284) while in subpopulation AFR AF = 0.047 (1952/41544). AF 95% confidence interval is 0.0453. There are 52 homozygotes in GnomAd4. There are 907 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	NM_007347.5	MANE Select	c.1085A>G	p.Tyr362Cys	missense	Exon 10 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.860A>G	p.Tyr287Cys	missense	Exon 10 of 21	NP_001239056.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP4E1	ENST00000261842.10	TSL:1 MANE Select	c.1085A>G	p.Tyr362Cys	missense	Exon 10 of 21	ENSP00000261842.5
	AP4E1	ENST00000560508.1	TSL:1	c.860A>G	p.Tyr287Cys	missense	Exon 10 of 21	ENSP00000452976.1
	AP4E1	ENST00000558439.5	TSL:1	n.*207A>G		non_coding_transcript_exon	Exon 10 of 21	ENSP00000452712.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2040 AN: 152166 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

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: 0.000220

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00353 AC: 887 AN: 251034 AF XY: 0.00250

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00137 AC: 1995 AN: 1461330 Hom.: 37 Cov.: 32 AF XY: 0.00119 AC XY: 866 AN XY: 727012

African (AFR) AF: 0.0493 AC: 1649 AN: 33424

American (AMR) AF: 0.00132 AC: 59 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111672

Other (OTH) AF: 0.00252 AC: 152 AN: 60368

GnomAD4 genome AF: 0.0134 AC: 2040 AN: 152284 Hom.: 52 Cov.: 32 AF XY: 0.0122 AC XY: 907 AN XY: 74482

African (AFR) AF: 0.0470 AC: 1952 AN: 41544

American (AMR) AF: 0.00333 AC: 51 AN: 15294

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68030

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.00517 Hom.: 31

Bravo AF: 0.0155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0492 AC: 216

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.052
Sift	Benign	0.20	T
Sift4G	Benign	0.18	T
Polyphen		0.075	B
Vest4		0.38
MVP		0.068
MPC		0.18
ClinPred		0.015	T
GERP RS		4.9
Varity_R		0.35
gMVP		0.44
Mutation Taster		=83/17	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: rs58909326; hg19: chr15-51233881;