rs75130619

Variant names:

• chr15-50997408-C-T
• rs75130619
• NM_007347.5:c.2429C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-50997408-C-T
• chr15-50997408-C-A

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.2429C>T​(p.Thr810Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,612,482 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: AP4E1 NM_007347.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.448
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021559596).
• BP6: Variant 15-50997408-C-T is Benign according to our data. Variant chr15-50997408-C-T is described in ClinVar as Benign. ClinVar VariationId is 128395.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 = 0.0111 (1689/152264) while in subpopulation AFR AF = 0.0394 (1637/41546). AF 95% confidence interval is 0.0378. There are 28 homozygotes in GnomAd4. There are 791 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.2429C>T	p.Thr810Ile	missense	Exon 18 of 21	NP_031373.2
	AP4E1	NM_001252127.2		c.2204C>T	p.Thr735Ile	missense	Exon 18 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.2429C>T	p.Thr810Ile	missense	Exon 18 of 21	ENSP00000261842.5	Q9UPM8-1
	AP4E1	ENST00000560508.1	TSL:1	c.2204C>T	p.Thr735Ile	missense	Exon 18 of 21	ENSP00000452976.1	Q9UPM8-2
	AP4E1	ENST00000558439.5	TSL:1	n.*1553C>T		non_coding_transcript_exon	Exon 18 of 21	ENSP00000452712.1	H0YK95

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1692 AN: 152146 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00290 AC: 724 AN: 249938 AF XY: 0.00207

Gnomad AFR exome AF: 0.0411

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.00106 AC: 1542 AN: 1460218 Hom.: 27 Cov.: 31 AF XY: 0.000880 AC XY: 639 AN XY: 726316

African (AFR) AF: 0.0393 AC: 1309 AN: 33338

American (AMR) AF: 0.00130 AC: 58 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000815 AC: 7 AN: 85918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111336

Other (OTH) AF: 0.00241 AC: 145 AN: 60286

GnomAD4 genome AF: 0.0111 AC: 1689 AN: 152264 Hom.: 28 Cov.: 32 AF XY: 0.0106 AC XY: 791 AN XY: 74452

African (AFR) AF: 0.0394 AC: 1637 AN: 41546

American (AMR) AF: 0.00268 AC: 41 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00432 Hom.: 27

Bravo AF: 0.0128

ESP6500AA AF: 0.0412 AC: 181

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00354 AC: 430

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	AP4E1-related disorder (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	0.067
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.5
DANN	Benign	0.93
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.45
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.028
Sift	Benign	0.22	T
Sift4G	Benign	0.12	T
Polyphen		0.012	B
Vest4		0.046
MVP		0.068
MPC		0.11
ClinPred		0.00073	T
GERP RS		2.2
Varity_R		0.035
gMVP		0.096
Mutation Taster		=97/3	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: rs75130619; hg19: chr15-51289605;