chr2-223777778-G-A

Variant names:

• chr2-223777778-G-A
• rs78536455
• NM_001039569.2:c.95C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (21 hom.)
• Consequence: AP1S3 NM_001039569.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 1.05
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• psoriasis 15, pustular, susceptibility to

  Inheritance: AD Classification: STRONG Submitted by: G2P
• pustulosis palmaris et plantaris

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• psoriasis 14, pustular

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286239 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1206126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039569.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S3	NM_001039569.2	MANE Select	c.95C>T	p.Thr32Ile	missense	Exon 2 of 5	NP_001034658.1	Q96PC3-4
	AP1S3	NR_110905.2		n.227C>T		non_coding_transcript_exon	Exon 2 of 6
	AP1S3	NR_110906.2		n.227C>T		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S3	ENST00000396654.7	TSL:2 MANE Select	c.95C>T	p.Thr32Ile	missense	Exon 2 of 5	ENSP00000379891.2	Q96PC3-4
	AP1S3	ENST00000443700.5	TSL:1	c.95C>T	p.Thr32Ile	missense	Exon 2 of 5	ENSP00000397155.1	Q96PC3-2
	AP1S3	ENST00000446015.6	TSL:1	c.95C>T	p.Thr32Ile	missense	Exon 2 of 4	ENSP00000388738.2	Q96PC3-1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152172 Hom.: 4 Cov.: 33

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

GnomAD2 exomes AF: 0.00354 AC: 884 AN: 249476 AF XY: 0.00332

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 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.: 21 Cov.: 31 AF XY: 0.00502 AC XY: 3648 AN XY: 727210

African (AFR) AF: 0.000807 AC: 27 AN: 33478

American (AMR) AF: 0.00427 AC: 191 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7145 AN: 1111956

Other (OTH) AF: 0.00422 AC: 255 AN: 60394

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152290 Hom.: 4 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74454

African (AFR) AF: 0.00125 AC: 52 AN: 41568

American (AMR) AF: 0.00699 AC: 107 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00635 AC: 432 AN: 68022

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00520 Hom.: 7

Bravo AF: 0.00412

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00697 AC: 57

ExAC AF: 0.00345 AC: 417

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00670

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.71
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.090
Sift	Benign	0.65	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.72
MVP		0.15
MPC		0.065
ClinPred		0.032	T
GERP RS		4.1
Varity_R		0.22
gMVP		0.12
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs78536455; hg19: chr2-224642495; COSMIC: COSV100525188;