rs116107386

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_001039569.2(AP1S3):c.11T>G(p.Phe4Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 1,613,370 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 13 hom., cov: 33)

Exomes 𝑓: 0.011 ( 114 hom. )

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 8.93

Publications

36 publications found

Variant links:

Genes affected

AP1S3 (HGNC:18971): (adaptor related protein complex 1 subunit sigma 3) This gene encodes a member of the adaptor-related protein complex 1, sigma subunit genes. The encoded protein is a component of adaptor protein complex 1 (AP-1), one of the AP complexes involved in claathrin-mediated vesicular transport from the Golgi or endosomes. Disruption of the pathway for display of HIV-1 antigens, which prevents recognition of the virus by cytotoxic T cells, has been shown to involve the AP-1 complex (PMID: 15569716). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

AP1S3 Gene-Disease associations (from GenCC):

psoriasis 15, pustular, susceptibility to
Inheritance: AD Classification: STRONG Submitted by: G2P
pustulosis palmaris et plantaris
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
psoriasis 14, pustular
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

AP1S3 links:

ENSG00000286239 (HGNC:):

ENSG00000286239 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.027574152).

BP6

Variant 2-223777862-A-C is Benign according to our data. Variant chr2-223777862-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
AP1S3	NM_001039569.2 link	c.11T>G	p.Phe4Cys	missense_variant	Exon 2 of 5	ENST00000396654.7	NP_001034658.1
AP1S3	XM_011510600.4 link	c.11T>G	p.Phe4Cys	missense_variant	Exon 2 of 4		XP_011508902.1
AP1S3	NR_110905.2 link	n.143T>G		non_coding_transcript_exon_variant	Exon 2 of 6
AP1S3	NR_110906.2 link	n.143T>G		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AP1S3	ENST00000396654.7 link	c.11T>G	p.Phe4Cys	missense_variant	Exon 2 of 5	2	NM_001039569.2	ENSP00000379891.2
ENSG00000286239	ENST00000650969.1 link	n.*975T>G		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000498456.1
ENSG00000286239	ENST00000650969.1 link	n.*975T>G		3_prime_UTR_variant	Exon 14 of 17			ENSP00000498456.1

Frequencies

GnomAD3 genomes

AF:

0.00865

AC:

1316

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.00693

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00759

AC:

1885

AN:

248296

AF XY:

0.00743

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00513

Gnomad ASJ exome

AF:

0.00410

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00401

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.00814

GnomAD4 exome

AF:

0.0111

AC:

16188

AN:

1461064

Hom.:

114

Cov.:

AF XY:

0.0109

AC XY:

7940

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33460

American (AMR)

AF:

0.00560

AC:

250

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00441

AC:

115

AN:

26094

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39672

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86088

European-Finnish (FIN)

AF:

0.00411

AC:

219

AN:

53344

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0134

AC:

14904

AN:

1111656

Other (OTH)

AF:

0.00780

AC:

471

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

730

1460

2191

2921

3651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

546

1092

1638

2184

2730

<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:

0.00864

AC:

1316

AN:

152306

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00284

AC:

118

AN:

41556

American (AMR)

AF:

0.00692

AC:

106

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00659

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0140

AC:

955

AN:

68024

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0121

Hom.:

Bravo

AF:

0.00881

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00266

AC:

ESP6500EA

AF:

0.0128

AC:

105

ExAC

AF:

0.00767

AC:

927

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Psoriasis 15, pustular, susceptibility to

Benign:1Other:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 01, 2014

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

AP1S3-related disorder

Benign:1

Jul 11, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AP1S3: PP3, BS1, BS2

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;T;T;T

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.028

T;T;T;T;T

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.4

M;M;.;M;.

PhyloP100

8.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.5

D;D;D;D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.017

D;D;D;D;D

Sift4G

Uncertain

0.0090

D;D;D;D;D

Vest4

0.98

ClinPred

0.052

GERP RS

5.8

Varity_R

0.88

gMVP

0.60

Mutation Taster

=17/83

disease causing

(source)

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

Publications

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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