Genetic Variant AP1S3:c.291+4128T>G (chr2-223771773-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001039569.2(AP1S3):c.291+4128T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,152 control chromosomes in the GnomAD database, including 8,407 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 8407 hom., cov: 33)

Consequence

AP1S3
NM_001039569.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.975

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.291+4128T>G	intron_variant	Intron 3 of 4	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	NR_110905.2 link	n.462+1540T>G	intron_variant	Intron 4 of 5
AP1S3	NR_110906.2 link	n.314+5918T>G	intron_variant	Intron 2 of 3
AP1S3	XM_011510600.4 link	c.291+4128T>G	intron_variant	Intron 3 of 3		XP_011508902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7 link	c.291+4128T>G		intron_variant	Intron 3 of 4	2	NM_001039569.2	ENSP00000379891.2		Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1255+4128T>G		intron_variant	Intron 15 of 16			ENSP00000498456.1		A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39724

AN:

152034

Hom.:

8382

Cov.:

show subpopulations

Gnomad AFR

AF:

0.542

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.582

Gnomad SAS

AF:

0.215

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.0832

Gnomad OTH

AF:

0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.262

AC:

39803

AN:

152152

Hom.:

8407

Cov.:

AF XY:

0.266

AC XY:

19822

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.542

AC:

22499

AN:

41476

American (AMR)

AF:

0.328

AC:

5019

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

449

AN:

3470

East Asian (EAS)

AF:

0.581

AC:

3006

AN:

5172

South Asian (SAS)

AF:

0.214

AC:

1032

AN:

4830

European-Finnish (FIN)

AF:

0.132

AC:

1403

AN:

10602

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0832

AC:

5655

AN:

68002

Other (OTH)

AF:

0.240

AC:

508

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1216

2433

3649

4866

6082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.140

Hom.:

1629

Bravo

AF:

0.294

Asia WGS

AF:

0.422

AC:

1469

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.0

(source)

DANN

Benign

0.75

PhyloP100

0.97

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over