Genetic Variant NM_001039569.2:c.183-170A>G (chr2-223776179-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001039569.2(AP1S3):c.183-170A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 701,156 control chromosomes in the GnomAD database, including 6,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.15 ( 3001 hom., cov: 32)

Exomes 𝑓: 0.088 ( 3493 hom. )

Consequence

AP1S3
NM_001039569.2 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.45

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-223776179-T-C is Benign according to our data. Variant chr2-223776179-T-C is described in ClinVar as [Benign]. Clinvar id is 2688467.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	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.183-170A>G	intron_variant	Intron 2 of 4	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	XM_011510600.4 link	c.183-170A>G	intron_variant	Intron 2 of 3		XP_011508902.1
AP1S3	NR_110905.2 link	n.315-170A>G	intron_variant	Intron 2 of 5
AP1S3	NR_110906.2 link	n.314+1512A>G	intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7 link	c.183-170A>G		intron_variant	Intron 2 of 4	2	NM_001039569.2	ENSP00000379891.2		Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1147-170A>G		intron_variant	Intron 14 of 16			ENSP00000498456.1		A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23171

AN:

152050

Hom.:

2997

Cov.:

show subpopulations

Gnomad AFR

AF:

0.344

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.0939

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.0870

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.118

AC:

17738

AN:

150432

Hom.:

1631

AF XY:

0.114

AC XY:

9138

AN XY:

80462

show subpopulations

Gnomad AFR exome

AF:

0.360

Gnomad AMR exome

AF:

0.163

Gnomad ASJ exome

AF:

0.0924

Gnomad EAS exome

AF:

0.276

Gnomad SAS exome

AF:

0.143

Gnomad FIN exome

AF:

0.0821

Gnomad NFE exome

AF:

0.0451

Gnomad OTH exome

AF:

0.0880

GnomAD4 exome

AF:

0.0876

AC:

48105

AN:

548988

Hom.:

3493

Cov.:

AF XY:

0.0885

AC XY:

26225

AN XY:

296250

show subpopulations

Gnomad4 AFR exome

AF:

0.340

Gnomad4 AMR exome

AF:

0.159

Gnomad4 ASJ exome

AF:

0.0932

Gnomad4 EAS exome

AF:

0.199

Gnomad4 SAS exome

AF:

0.139

Gnomad4 FIN exome

AF:

0.0795

Gnomad4 NFE exome

AF:

0.0456

Gnomad4 OTH exome

AF:

0.0965

GnomAD4 genome

AF:

0.152

AC:

23201

AN:

152168

Hom.:

3001

Cov.:

AF XY:

0.155

AC XY:

11521

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.344

Gnomad4 AMR

AF:

0.135

Gnomad4 ASJ

AF:

0.0939

Gnomad4 EAS

AF:

0.253

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.0870

Gnomad4 NFE

AF:

0.0465

Gnomad4 OTH

AF:

0.131

Alfa

AF:

0.103

Hom.:

433

Bravo

AF:

0.167

Asia WGS

AF:

0.230

AC:

804

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

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 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.22

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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