X-15827336-C-T

Position:

chrX-15827336-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001272071.2(AP1S2):c.472G>A(p.Gly158Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,207,008 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000014 ( 0 hom. 3 hem. )

Consequence

AP1S2
NM_001272071.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.38

Variant links:

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]

AP1S2 links:

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]

ZRSR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1S2	NM_001272071.2 link	c.472G>A	p.Gly158Arg	missense_variant	6/6	ENST00000672987.1	NP_001259000.1	A0A5F9ZHW1
AP1S2	NM_003916.5 link	c.463G>A	p.Gly155Arg	missense_variant	5/5		NP_003907.3	P56377-1Q549M9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1S2	ENST00000672987.1 link	c.472G>A	p.Gly158Arg	missense_variant	6/6		NM_001272071.2	ENSP00000500695.1		A0A5F9ZHW1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111832

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34016

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1095176

Hom.:

Cov.:

AF XY:

0.00000831

AC XY:

AN XY:

360876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000167

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111832

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

34016

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 07, 2020

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with AP1S2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 155 of the AP1S2 protein (p.Gly155Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.081

T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.9

M;.

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.4

D;.

REVEL

Benign

0.28

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.88

P;.

Vest4

0.50

MutPred

0.40

Gain of solvent accessibility (P = 0.0306);.;

MVP

0.42

MPC

2.3

ClinPred

0.99

GERP RS

5.6

Varity_R

0.60

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.40

Position offset: 36

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over