NM_001039569.2:c.95C>T

Variant names:

Variant summary

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

The NM_001039569.2(AP1S3):c.95C>T(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,614,086 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 21 hom. )

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:4

Conservation

PhyloP100: 1.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010055482).

BP6

Variant 2-223777778-G-A is Benign according to our data. Variant chr2-223777778-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1206126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-223777778-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 618 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.95C>T	p.Thr32Ile	missense_variant	Exon 2 of 5	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	XM_011510600.4 link	c.95C>T	p.Thr32Ile	missense_variant	Exon 2 of 4		XP_011508902.1
AP1S3	NR_110905.2 link	n.227C>T		non_coding_transcript_exon_variant	Exon 2 of 6
AP1S3	NR_110906.2 link	n.227C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP1S3	ENST00000396654.7 link	c.95C>T	p.Thr32Ile	missense_variant	Exon 2 of 5	2	NM_001039569.2	ENSP00000379891.2	Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1059C>T		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000498456.1	A0A494C0A6
ENSG00000286239	ENST00000650969.1 link	n.*1059C>T		3_prime_UTR_variant	Exon 14 of 17			ENSP00000498456.1	A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

618

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00354

AC:

884

AN:

249476

Hom.:

AF XY:

0.00332

AC XY:

450

AN XY:

135356

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00432

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00130

Gnomad NFE exome

AF:

0.00582

Gnomad OTH exome

AF:

0.00396

GnomAD4 exome

AF:

0.00527

AC:

7703

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

3648

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00427

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.00643

Gnomad4 OTH exome

AF:

0.00422

GnomAD4 genome

AF:

0.00406

AC:

618

AN:

152290

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00635

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00564

Hom.:

Bravo

AF:

0.00412

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000270

AC:

ESP6500EA

AF:

0.00697

AC:

ExAC

AF:

0.00345

AC:

417

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00670

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.034

.;.;T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Benign

0.0042

MetaRNN

Benign

0.010

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.67

N;N;.;N;.

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.7

D;D;D;D;N

REVEL

Benign

0.090

Sift

Benign

0.65

T;T;T;T;T

Sift4G

Benign

0.54

T;T;T;T;T

Polyphen

0.0

.;B;.;B;.

Vest4

0.72

MVP

0.15

MPC

0.065

ClinPred

0.032

GERP RS

4.1

Varity_R

0.22

gMVP

0.12

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