chr2-223777776-G-A

Position:

chr2-223777776-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PS1_ModerateBP4_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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

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:5O:1

Conservation

PhyloP100: 2.68

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 Benign. Variant got -14 ACMG points.

PS1

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

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 [Likely_benign]. Clinvar id is 160375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-223777776-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-223777776-G-A is described in Lovd as [Pathogenic]. Variant chr2-223777776-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1093 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
AP1S3	NM_001039569.2 linkuse as main transcript	c.97C>T	p.Arg33Trp	missense_variant	2/5	ENST00000396654.7
AP1S3	XM_011510600.4 linkuse as main transcript	c.97C>T	p.Arg33Trp	missense_variant	2/4
AP1S3	NR_110905.2 linkuse as main transcript	n.229C>T		non_coding_transcript_exon_variant	2/6
AP1S3	NR_110906.2 linkuse as main transcript	n.229C>T		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.97C>T	p.Arg33Trp	missense_variant	2/5	2	NM_001039569.2	P1	Q96PC3-4

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

GnomAD3 exomes

AF:

0.00760

AC:

1896

AN:

249412

Hom.:

AF XY:

0.00771

AC XY:

1043

AN XY:

135318

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 SAS exome

AF:

0.00441

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

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00407

Gnomad4 ASJ exome

AF:

0.00352

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00415

Gnomad4 FIN exome

AF:

0.0108

Gnomad4 NFE exome

AF:

0.0113

Gnomad4 OTH exome

AF:

0.00964

GnomAD4 genome

AF:

0.00718

AC:

1093

AN:

152236

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

512

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00181

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00478

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00989

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

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	AP1S3: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Psoriasis 15, pustular, susceptibility to

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 20, 2022	- -
risk factor, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF 1.2%. Limited evidence for gene-disease association. -

AP1S3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 02, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

.;.;T;T;T

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D;D;D;D

MetaRNN

Benign

0.030

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

3.8

H;H;.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.6

D;D;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.011

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

1.0

.;D;.;D;.

Vest4

0.92

MVP

0.50

MPC

0.39

ClinPred

0.27

GERP RS

4.9

Varity_R

0.74

gMVP

0.47

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

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