rs11902103

Variant names:

• chr2-223776146-C-T
• rs11902103
• NM_001039569.2:c.183-137G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001039569.2(AP1S3):​c.183-137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 718,880 control chromosomes in the GnomAD database, including 6,540 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2998 hom., cov: 33)
  • Exomes 𝑓: 0.087 (3542 hom.)
• Consequence: AP1S3 NM_001039569.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.306
• Publications: 4 publications found

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

ENSG00000286239 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-223776146-C-T is Benign according to our data. Variant chr2-223776146-C-T is described in ClinVar as [Benign]. Clinvar id is 2628301.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2	c.183-137G>A		intron_variant	Intron 2 of 4	ENST00000396654.7	NP_001034658.1
AP1S3	NR_110905.2	n.315-137G>A		intron_variant	Intron 2 of 5
AP1S3	NR_110906.2	n.314+1545G>A		intron_variant	Intron 2 of 3
AP1S3	XM_011510600.4	c.183-137G>A		intron_variant	Intron 2 of 3		XP_011508902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7	c.183-137G>A		intron_variant	Intron 2 of 4	2	NM_001039569.2	ENSP00000379891.2
ENSG00000286239	ENST00000650969.1	n.*1147-137G>A		intron_variant	Intron 14 of 16			ENSP00000498456.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23161 AN: 152040 Hom.: 2994 Cov.: 33

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.117 AC: 18018 AN: 154208 AF XY: 0.112

Gnomad AFR exome AF: 0.360

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.0818

Gnomad NFE exome AF: 0.0448

Gnomad OTH exome AF: 0.0886

GnomAD4 exome AF: 0.0868 AC: 49175 AN: 566722 Hom.: 3542 Cov.: 5 AF XY: 0.0875 AC XY: 26765 AN XY: 305738

African (AFR) AF: 0.339 AC: 5350 AN: 15792

American (AMR) AF: 0.158 AC: 5453 AN: 34518

Ashkenazi Jewish (ASJ) AF: 0.0924 AC: 1835 AN: 19854

East Asian (EAS) AF: 0.198 AC: 6277 AN: 31726

South Asian (SAS) AF: 0.139 AC: 8612 AN: 62062

European-Finnish (FIN) AF: 0.0790 AC: 3801 AN: 48124

Middle Eastern (MID) AF: 0.0845 AC: 343 AN: 4058

European-Non Finnish (NFE) AF: 0.0455 AC: 14559 AN: 320052

Other (OTH) AF: 0.0964 AC: 2945 AN: 30536

GnomAD4 genome AF: 0.152 AC: 23190 AN: 152158 Hom.: 2998 Cov.: 33 AF XY: 0.155 AC XY: 11513 AN XY: 74388

African (AFR) AF: 0.344 AC: 14251 AN: 41474

American (AMR) AF: 0.135 AC: 2059 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 326 AN: 3472

East Asian (EAS) AF: 0.254 AC: 1313 AN: 5174

South Asian (SAS) AF: 0.151 AC: 726 AN: 4822

European-Finnish (FIN) AF: 0.0868 AC: 921 AN: 10608

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3161 AN: 68014

Other (OTH) AF: 0.131 AC: 276 AN: 2106

Alfa AF: 0.112 Hom.: 585

Bravo AF: 0.167

Asia WGS AF: 0.230 AC: 802 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.44
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11902103; hg19: chr2-224640863; COSMIC: COSV57510919;