rs116107386

chr2-223777862-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PS1_Moderate PP3 BP4_Strong BS2

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 8.93

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]

ACMG classification

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 GnomAd at 1316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP1S3	NM_001039569.2	c.11T>G	p.Phe4Cys	missense_variant	2/5	ENST00000396654.7
AP1S3	XM_011510600.4	c.11T>G	p.Phe4Cys	missense_variant	2/4
AP1S3	NR_110905.2	n.143T>G		non_coding_transcript_exon_variant	2/6
AP1S3	NR_110906.2	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	c.11T>G	p.Phe4Cys	missense_variant	2/5	2	NM_001039569.2	P1

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1316 AN: 152188 Hom.: 13 Cov.: 33

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.: 19 AF XY: 0.00743 AC XY: 1001 AN XY: 134682

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.: 31 AF XY: 0.0109 AC XY: 7940 AN XY: 726760

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.: 13 Cov.: 33 AF XY: 0.00822 AC XY: 612 AN XY: 74486

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.: 29

Bravo AF: 0.00881

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00266 AC: 10

ESP6500EA AF: 0.0128 AC: 105

ExAC AF: 0.00767 AC: 927

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0120

EpiControl AF: 0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

AP1S3-related disorder Benign:1

Likely benign, criteria provided, single submitter

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

Sep 01, 2023

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	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
MetaRNN	Benign	0.028	T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
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	T
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

Other links and lift over

dbSNP: rs116107386; hg19: chr2-224642579; COSMIC: COSV57513248;