chr2-223775957-A-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001039569.2(AP1S3):c.235T>G(p.Leu79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,614,210 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 1 hom. )

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.14

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012252778).

BP6

Variant 2-223775957-A-C is Benign according to our data. Variant chr2-223775957-A-C is described in ClinVar as [Benign]. Clinvar id is 3043974.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-223775957-A-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 422 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.235T>G	p.Leu79Val	missense_variant	Exon 3 of 5	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	XM_011510600.4 link	c.235T>G	p.Leu79Val	missense_variant	Exon 3 of 4		XP_011508902.1
AP1S3	NR_110905.2 link	n.367T>G		non_coding_transcript_exon_variant	Exon 3 of 6
AP1S3	NR_110906.2 link	n.314+1734T>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP1S3	ENST00000396654.7 link	c.235T>G	p.Leu79Val	missense_variant	Exon 3 of 5	2	NM_001039569.2	ENSP00000379891.2	Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1199T>G		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000498456.1	A0A494C0A6
ENSG00000286239	ENST00000650969.1 link	n.*1199T>G		3_prime_UTR_variant	Exon 15 of 17			ENSP00000498456.1	A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

422

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00950

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000709

AC:

177

AN:

249498

Hom.:

AF XY:

0.000421

AC XY:

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000266

AC:

389

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.00277

AC:

422

AN:

152346

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00948

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000575

Hom.:

Bravo

AF:

0.00295

ESP6500AA

AF:

0.00883

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000919

AC:

111

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

AP1S3-related disorder

Benign:1

Jun 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.020

.;.;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.1

M;M;M;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.0030, 0.96

.;B;D;.

Vest4

0.61

MVP

0.24

MPC

0.20

ClinPred

0.027

GERP RS

3.6

Varity_R

0.22

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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