X-15827335-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001272071.2(AP1S2):c.473G>A(p.Gly158Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G158R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: AP1S2 NM_001272071.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

Genes affected

AP1S2 (HGNC:560): (adaptor related protein complex 1 subunit sigma 2) Adaptor protein complex 1 is found at the cytoplasmic face of coated vesicles located at the Golgi complex, where it mediates both the recruitment of clathrin to the membrane and the recognition of sorting signals within the cytosolic tails of transmembrane receptors. This complex is a heterotetramer composed of two large, one medium, and one small adaptin subunit. The protein encoded by this gene serves as the small subunit of this complex and is a member of the adaptin protein family. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

ZRSR2 (HGNC:23019): (zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2) This gene encodes an essential splicing factor. The encoded protein associates with the U2 auxiliary factor heterodimer, which is required for the recognition of a functional 3' splice site in pre-mRNA splicing, and may play a role in network interactions during spliceosome assembly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP1S2	NM_001272071.2	c.473G>A	p.Gly158Glu	missense_variant	6/6	ENST00000672987.1
AP1S2	NM_003916.5	c.464G>A	p.Gly155Glu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP1S2	ENST00000672987.1	c.473G>A	p.Gly158Glu	missense_variant	6/6		NM_001272071.2	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 11, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with AP1S2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 155 of the AP1S2 protein (p.Gly155Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.076	T;T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.78	P;.
Vest4		0.35
MutPred		0.35		Gain of solvent accessibility (P = 0.0837);.;
MVP		0.26
MPC		1.8
ClinPred		0.93	D
GERP RS		3.8
Varity_R		0.61
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-15845458;