chr2-223775944-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001039569.2(AP1S3):c.248T>C(p.Ile83Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000614 in 1,614,180 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 12 hom. )

Consequence

AP1S3
NM_001039569.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.22

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013260633).

BP6

Variant 2-223775944-A-G is Benign according to our data. Variant chr2-223775944-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1301563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2 link	c.248T>C	p.Ile83Thr	missense_variant	Exon 3 of 5	ENST00000396654.7	NP_001034658.1	Q96PC3-4
AP1S3	XM_011510600.4 link	c.248T>C	p.Ile83Thr	missense_variant	Exon 3 of 4		XP_011508902.1
AP1S3	NR_110905.2 link	n.380T>C		non_coding_transcript_exon_variant	Exon 3 of 6
AP1S3	NR_110906.2 link	n.314+1747T>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP1S3	ENST00000396654.7 link	c.248T>C	p.Ile83Thr	missense_variant	Exon 3 of 5	2	NM_001039569.2	ENSP00000379891.2	Q96PC3-4
ENSG00000286239	ENST00000650969.1 link	n.*1212T>C		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000498456.1	A0A494C0A6
ENSG00000286239	ENST00000650969.1 link	n.*1212T>C		3_prime_UTR_variant	Exon 15 of 17			ENSP00000498456.1	A0A494C0A6

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00139

AC:

347

AN:

249500

Hom.:

AF XY:

0.00191

AC XY:

259

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000636

AC:

930

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000942

AC XY:

685

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0103

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000400

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0122

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.00167

AC:

202

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Psoriasis 15, pustular, susceptibility to

Benign:1

Aug 27, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

.;.;T;T

Eigen

Benign

-0.045

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T;T;T

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Benign

0.098

Sift

Benign

0.081

T;T;T;T

Sift4G

Benign

0.26

T;T;T;T

Polyphen

0.0010, 0.55

.;B;P;.

Vest4

0.49

MutPred

0.58

Gain of disorder (P = 0.1009);Gain of disorder (P = 0.1009);Gain of disorder (P = 0.1009);Gain of disorder (P = 0.1009);

MVP

0.78

MPC

0.089

ClinPred

0.039

GERP RS

3.7

Varity_R

0.46

gMVP

0.37

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