Genetic Variant AP1S3:p.Glu89Asp (chr2-223775925-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001039569.2(AP1S3):c.267G>C(p.Glu89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E89E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.9

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	UniProt
AP1S3	NM_001039569.2	MANE Select	c.267G>C	p.Glu89Asp	missense	Exon 3 of 5	NP_001034658.1	Q96PC3-4
AP1S3	NR_110905.2		n.399G>C		non_coding_transcript_exon	Exon 3 of 6
AP1S3	NR_110906.2		n.314+1766G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP1S3	ENST00000396654.7	TSL:2 MANE Select	c.267G>C	p.Glu89Asp	missense	Exon 3 of 5	ENSP00000379891.2	Q96PC3-4
AP1S3	ENST00000443700.5	TSL:1	c.267G>C	p.Glu89Asp	missense	Exon 3 of 5	ENSP00000397155.1	Q96PC3-2
AP1S3	ENST00000446015.6	TSL:1	c.267G>C	p.Glu89Asp	missense	Exon 3 of 4	ENSP00000388738.2	Q96PC3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

4.2

PhyloP100

1.6

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.94

Vest4

0.93

MutPred

0.78

Loss of ubiquitination at K93 (P = 0.1741)

MVP

0.83

MPC

0.36

ClinPred

1.0

GERP RS

5.1

Varity_R

0.81

gMVP

0.55

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over