NM_001039569.2:c.235T>G

Variant names:

• chr2-223775957-A-C
• rs34353588
• NM_001039569.2:c.235T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: AP1S3 NM_001039569.2 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.14
• Publications: 1 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: Likely_benign. The variant received -5 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 VariationId is 3043974.Status of the report is no_assertion_criteria_provided, 0 stars.

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.235T>G	p.Leu79Val	missense	Exon 3 of 5	NP_001034658.1	Q96PC3-4
	AP1S3	NR_110905.2		n.367T>G		non_coding_transcript_exon	Exon 3 of 6
	AP1S3	NR_110906.2		n.314+1734T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S3	ENST00000396654.7	TSL:2 MANE Select	c.235T>G	p.Leu79Val	missense	Exon 3 of 5	ENSP00000379891.2	Q96PC3-4
	AP1S3	ENST00000443700.5	TSL:1	c.235T>G	p.Leu79Val	missense	Exon 3 of 5	ENSP00000397155.1	Q96PC3-2
	AP1S3	ENST00000446015.6	TSL:1	c.235T>G	p.Leu79Val	missense	Exon 3 of 4	ENSP00000388738.2	Q96PC3-1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152228 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000709 AC: 177 AN: 249498 AF XY: 0.000421

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 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.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 147 AN XY: 727234

African (AFR) AF: 0.0102 AC: 343 AN: 33478

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111996

Other (OTH) AF: 0.000381 AC: 23 AN: 60392

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74502

African (AFR) AF: 0.00948 AC: 394 AN: 41580

American (AMR) AF: 0.00157 AC: 24 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00108 Hom.: 4

Bravo AF: 0.00295

ESP6500AA AF: 0.00883 AC: 34

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000919 AC: 111

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	AP1S3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.0030	B
Vest4		0.61
MVP		0.24
MPC		0.20
ClinPred		0.027	T
GERP RS		3.6
Varity_R		0.22
gMVP		0.36
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs34353588; hg19: chr2-224640674;