rs756177532

Variant names:

• chr2-223776002-T-C
• rs756177532
• NM_001039569.2:c.190A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001039569.2(AP1S3):​c.190A>G​(p.Ser64Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP1S3 NM_001039569.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

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]

ENSG00000286239 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S3	NM_001039569.2	c.190A>G	p.Ser64Gly	missense_variant	Exon 3 of 5	ENST00000396654.7	NP_001034658.1
AP1S3	XM_011510600.4	c.190A>G	p.Ser64Gly	missense_variant	Exon 3 of 4		XP_011508902.1
AP1S3	NR_110905.2	n.322A>G		non_coding_transcript_exon_variant	Exon 3 of 6
AP1S3	NR_110906.2	n.314+1689A>G		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S3	ENST00000396654.7	c.190A>G	p.Ser64Gly	missense_variant	Exon 3 of 5	2	NM_001039569.2	ENSP00000379891.2
ENSG00000286239	ENST00000650969.1	n.*1154A>G		non_coding_transcript_exon_variant	Exon 15 of 17			ENSP00000498456.1
ENSG00000286239	ENST00000650969.1	n.*1154A>G		3_prime_UTR_variant	Exon 15 of 17			ENSP00000498456.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248502 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190A>G (p.S64G) alteration is located in exon 3 (coding exon 3) of the AP1S3 gene. This alteration results from a A to G substitution at nucleotide position 190, causing the serine (S) at amino acid position 64 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.0090	T
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L;L;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.081	T;T;D;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.018, 1.0	.;B;D;.
Vest4		0.82
MutPred		0.71		Loss of stability (P = 0.0507);Loss of stability (P = 0.0507);Loss of stability (P = 0.0507);Loss of stability (P = 0.0507);
MVP		0.44
MPC		0.37
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.77
gMVP		0.41

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

Other links and lift over

dbSNP: rs756177532; hg19: chr2-224640719;