2-223777862-A-C

Position:

chr2-223777862-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PS1_ModeratePP3BP4_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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

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 criteria provided, single submitter B:2O:1

Conservation

PhyloP100: 8.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PS1

Transcript NM_001039569.2 (AP1S3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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).

BS2

High AC in GnomAd4 at 1316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP1S3	NM_001039569.2 linkuse as main transcript	c.11T>G	p.Phe4Cys	missense_variant	2/5	ENST00000396654.7
AP1S3	XM_011510600.4 linkuse as main transcript	c.11T>G	p.Phe4Cys	missense_variant	2/4
AP1S3	NR_110905.2 linkuse as main transcript	n.143T>G		non_coding_transcript_exon_variant	2/6
AP1S3	NR_110906.2 linkuse as main transcript	n.143T>G		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP1S3	ENST00000396654.7 linkuse as main transcript	c.11T>G	p.Phe4Cys	missense_variant	2/5	2	NM_001039569.2	P1	Q96PC3-4

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

GnomAD3 exomes

AF:

0.00759

AC:

1885

AN:

248296

Hom.:

AF XY:

0.00743

AC XY:

1001

AN XY:

134682

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 SAS exome

AF:

0.00178

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

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00560

Gnomad4 ASJ exome

AF:

0.00441

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00179

Gnomad4 FIN exome

AF:

0.00411

Gnomad4 NFE exome

AF:

0.0134

Gnomad4 OTH exome

AF:

0.00780

GnomAD4 genome

AF:

0.00864

AC:

1316

AN:

152306

Hom.:

Cov.:

AF XY:

0.00822

AC XY:

612

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.00692

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00659

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0125

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

Submissions summary: Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

AP1S3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2022

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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

AP1S3: PP3, BS1, BS2 -

Psoriasis 15, pustular, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 01, 2014

- -

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

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;.;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;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

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

Polyphen

1.0

.;D;.;D;.

Vest4

0.98

MVP

0.67

MPC

0.45

ClinPred

0.052

GERP RS

5.8

Varity_R

0.88

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over