2-223775952-C-T

Variant names:

• chr2-223775952-C-T
• rs200314987
• NM_001039569.2:c.240G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_001039569.2(AP1S3):​c.240G>A​(p.Thr80Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: AP1S3 NM_001039569.2 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.479
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-223775952-C-T is Benign according to our data. Variant chr2-223775952-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3050716.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.479 with no splicing effect.

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.240G>A	p.Thr80Thr	synonymous	Exon 3 of 5	NP_001034658.1	Q96PC3-4
	AP1S3	NR_110905.2		n.372G>A		non_coding_transcript_exon	Exon 3 of 6
	AP1S3	NR_110906.2		n.314+1739G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S3	ENST00000396654.7	TSL:2 MANE Select	c.240G>A	p.Thr80Thr	synonymous	Exon 3 of 5	ENSP00000379891.2	Q96PC3-4
	AP1S3	ENST00000443700.5	TSL:1	c.240G>A	p.Thr80Thr	synonymous	Exon 3 of 5	ENSP00000397155.1	Q96PC3-2
	AP1S3	ENST00000446015.6	TSL:1	c.240G>A	p.Thr80Thr	synonymous	Exon 3 of 4	ENSP00000388738.2	Q96PC3-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 249486 AF XY: 0.000170

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000254 AC: 372 AN: 1461842 Hom.: 1 Cov.: 31 AF XY: 0.000252 AC XY: 183 AN XY: 727218

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1111978

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74468

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.31
CADD	Benign	3.2
DANN	Benign	0.70
PhyloP100		-0.48
Mutation Taster		=96/4	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: rs200314987; hg19: chr2-224640669; COSMIC: COSV100525482;