NM_001128126.3:c.29A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001128126.3(AP4S1):c.29A>G(p.Lys10Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000818 in 1,614,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 2 hom. )

Consequence

AP4S1
NM_001128126.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 4.09

Publications

5 publications found

Variant links:

Genes affected

AP4S1 (HGNC:575): (adaptor related protein complex 4 subunit sigma 1) This gene encodes a member of the adaptor complexes small 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 the small subunit of adaptor protein complex-4, which is associated with both clathrin- and nonclathrin-coated vesicles. Mutations in this gene are associated with spastic quadriplegic cerebral palsy-6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Dec 2011]

AP4S1 Gene-Disease associations (from GenCC):

AP-4 deficiency syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hereditary spastic paraplegia 52
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
AP4-related intellectual disability and spastic paraplegia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP4S1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015460998).

BP6

Variant 14-31066225-A-G is Benign according to our data. Variant chr14-31066225-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434248.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP4S1	NM_001128126.3 link	c.29A>G	p.Lys10Arg	missense_variant	Exon 2 of 6	ENST00000542754.7	NP_001121598.1	Q9Y587-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP4S1	ENST00000542754.7 link	c.29A>G	p.Lys10Arg	missense_variant	Exon 2 of 6	1	NM_001128126.3	ENSP00000438170.2		Q9Y587-1

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000621

AC:

156

AN:

251350

AF XY:

0.000559

show subpopulations

Gnomad AFR exome

AF:

0.000863

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000625

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000811

AC:

1185

AN:

1461734

Hom.:

Cov.:

AF XY:

0.000771

AC XY:

561

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33468

American (AMR)

AF:

0.00170

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000934

AC:

1038

AN:

1111936

Other (OTH)

AF:

0.000696

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000886

AC:

135

AN:

152330

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41580

American (AMR)

AF:

0.00399

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000738

Hom.:

Bravo

AF:

0.000979

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 23, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Apr 15, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Dec 28, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 52

Uncertain:1

Apr 13, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Spastic paraplegia

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jul 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

.;T;T;.;T;.;.;T;.;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

D;.;.;D;D;D;.;D;T;D

M_CAP

Benign

0.0017

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.065

.;N;N;N;.;N;N;.;N;N

PhyloP100

4.1

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

N;.;N;N;N;N;N;N;N;.

REVEL

Benign

0.096

Sift

Benign

1.0

T;.;T;T;T;T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T

Polyphen

0.046, 0.032

.;B;B;.;.;B;.;.;.;B

Vest4

0.28, 0.28, 0.29, 0.31, 0.30, 0.31

MVP

0.28

MPC

0.13

ClinPred

0.030

GERP RS

4.8

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.20

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over