rs138292988

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001039569.2(AP1S3):c.97C>T(p.Arg33Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00961 in 1,614,002 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0099 ( 102 hom. )

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 2.68

Publications

28 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029742658).

BP6

Variant 2-223777776-G-A is Benign according to our data. Variant chr2-223777776-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039569.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP1S3	NM_001039569.2	MANE Select	c.97C>T	p.Arg33Trp	missense	Exon 2 of 5	NP_001034658.1
AP1S3	NR_110905.2		n.229C>T		non_coding_transcript_exon	Exon 2 of 6
AP1S3	NR_110906.2		n.229C>T		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AP1S3	ENST00000396654.7	TSL:2 MANE Select	c.97C>T	p.Arg33Trp	missense	Exon 2 of 5	ENSP00000379891.2
AP1S3	ENST00000443700.5	TSL:1	c.97C>T	p.Arg33Trp	missense	Exon 2 of 5	ENSP00000397155.1
AP1S3	ENST00000446015.6	TSL:1	c.97C>T	p.Arg33Trp	missense	Exon 2 of 4	ENSP00000388738.2

Frequencies

GnomAD3 genomes

AF:

0.00719

AC:

1093

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00426

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00760

AC:

1896

AN:

249412

AF XY:

0.00771

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00409

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0106

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00892

GnomAD4 exome

AF:

0.00986

AC:

14417

AN:

1461766

Hom.:

102

Cov.:

AF XY:

0.00972

AC XY:

7067

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33480

American (AMR)

AF:

0.00407

AC:

182

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00352

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39688

South Asian (SAS)

AF:

0.00415

AC:

358

AN:

86244

European-Finnish (FIN)

AF:

0.0108

AC:

579

AN:

53400

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0113

AC:

12563

AN:

1111950

Other (OTH)

AF:

0.00964

AC:

582

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

740

1480

2219

2959

3699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

446

892

1338

1784

2230

<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:

0.00718

AC:

1093

AN:

152236

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

512

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00181

AC:

AN:

41534

American (AMR)

AF:

0.00425

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00478

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

794

AN:

68024

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

112

169

225

281

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:

0.00977

Hom.:

Bravo

AF:

0.00690

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00189

AC:

ESP6500EA

AF:

0.0116

AC:

ExAC

AF:

0.00796

AC:

962

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00913

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

AP1S3-related disorder (1)

Psoriasis 15, pustular, susceptibility to (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.030

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.8

PhyloP100

2.7

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.011

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.92

MVP

0.50

MPC

0.39

ClinPred

0.27

GERP RS

4.9

Varity_R

0.74

gMVP

0.47

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over