rs587776738

Variant names:

• chrX-15846012-CTGTA-C
• rs587776738
• NM_001272071.2:c.180-5_180-2delTACA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001272071.2(AP1S2):​c.180-5_180-2delTACA variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: AP1S2 NM_001272071.2 splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 5

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• X-linked syndromic complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• fried syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-15846012-CTGTA-C is Pathogenic according to our data. Variant chrX-15846012-CTGTA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10779.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272071.2. 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
	AP1S2	NM_001272071.2	MANE Select	c.180-5_180-2delTACA		splice_acceptor splice_region intron	N/A	NP_001259000.1	A0A5F9ZHW1
	AP1S2	NM_001369007.1		c.180-5_180-2delTACA		splice_acceptor splice_region intron	N/A	NP_001355936.1	A6NH01
	AP1S2	NM_001440864.1		c.180-5_180-2delTACA		splice_acceptor splice_region intron	N/A	NP_001427793.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP1S2	ENST00000672987.1	MANE Select	c.180-5_180-2delTACA		splice_acceptor splice_region intron	N/A	ENSP00000500695.1	A0A5F9ZHW1
	AP1S2	ENST00000329235.6	TSL:1	c.180-5_180-2delTACA		splice_acceptor splice_region intron	N/A	ENSP00000328789.2	P56377-1
	AP1S2	ENST00000545766.7	TSL:1	c.48-5_48-2delTACA		splice_acceptor splice_region intron	N/A	ENSP00000444957.3	F6SFB5

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Pettigrew syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs587776738; hg19: chrX-15864135;