Genetic Variant AP1S3:c.292-4861C>T (chr2-223770211-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001039569.2(AP1S3):c.292-4861C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,550,816 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

AP1S3
NM_001039569.2 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.767

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:

ENSG00000286239 (HGNC:):

ENSG00000286239 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006602764).

BP6

Variant 2-223770211-G-A is Benign according to our data. Variant chr2-223770211-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3388110.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.292-4861C>T	intron_variant	Intron 3 of 4	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	XM_011510600.4 link	c.291+5690C>T	intron_variant	Intron 3 of 3		XP_011508902.1
AP1S3	NR_110905.2 link	n.462+3102C>T	intron_variant	Intron 4 of 5
AP1S3	NR_110906.2 link	n.315-4861C>T	intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7 link	c.292-4861C>T		intron_variant	Intron 3 of 4	2	NM_001039569.2	ENSP00000379891.2		Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1256-4861C>T		intron_variant	Intron 15 of 16			ENSP00000498456.1		A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

197

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00106

AC:

159

AN:

150552

Hom.:

AF XY:

0.000965

AC XY:

AN XY:

80790

show subpopulations

Gnomad AFR exome

AF:

0.000287

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000444

Gnomad FIN exome

AF:

0.000236

Gnomad NFE exome

AF:

0.00163

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.00182

AC:

2545

AN:

1398604

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

1178

AN XY:

689814

show subpopulations

Gnomad4 AFR exome

AF:

0.000253

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000530

Gnomad4 FIN exome

AF:

0.000352

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.00248

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152212

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00135

ExAC

AF:

0.00111

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AP1S3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

Eigen

Benign

0.045

Eigen_PC

Benign

0.043

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.79

PROVEAN

Benign

-2.0

REVEL

Benign

0.029

Sift

Uncertain

0.019

Sift4G

Uncertain

0.018

Vest4

0.11

MVP

0.47

ClinPred

0.026

GERP RS

2.8

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

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