rs770199415

Variant names:

• chrX-15845524-G-A
• rs770199415
• NM_001272071.2:c.289-8C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-15845524-G-A
• chrX-15845524-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001272071.2(AP1S2):​c.289-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,184,871 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00010 (0 hom. 39 hem.)
• Consequence: AP1S2 NM_001272071.2 splice_region, intron
• Scores: Splicing: ADA: 0.00005072
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.606
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• X-linked syndromic intellectual disability

  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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-15845524-G-A is Benign according to our data. Variant chrX-15845524-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 5 XL gene

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.289-8C>T		splice_region intron	N/A	NP_001259000.1
	AP1S2	NM_001369007.1		c.289-8C>T		splice_region intron	N/A	NP_001355936.1
	AP1S2	NM_001440864.1		c.289-8C>T		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.289-8C>T		splice_region intron	N/A	ENSP00000500695.1
	AP1S2	ENST00000329235.6	TSL:1	c.289-8C>T		splice_region intron	N/A	ENSP00000328789.2
	AP1S2	ENST00000545766.7	TSL:1	c.157-8C>T		splice_region intron	N/A	ENSP00000444957.3

Frequencies

GnomAD3 genomes AF: 0.000168 AC: 18 AN: 107293 Hom.: 0 Cov.: 22

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: 0.000347

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000152 AC: 25 AN: 164646 AF XY: 0.0000513

Gnomad AFR exome AF: 0.0000836

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000648

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 110 AN: 1077578 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 39 AN XY: 351766

African (AFR) AF: 0.0000402 AC: 1 AN: 24862

American (AMR) AF: 0.0000320 AC: 1 AN: 31232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18649

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29838

South Asian (SAS) AF: 0.00 AC: 0 AN: 49988

European-Finnish (FIN) AF: 0.0000500 AC: 2 AN: 40008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3689

European-Non Finnish (NFE) AF: 0.000123 AC: 103 AN: 834235

Other (OTH) AF: 0.0000444 AC: 2 AN: 45077

GnomAD4 genome AF: 0.000168 AC: 18 AN: 107293 Hom.: 0 Cov.: 22 AF XY: 0.000162 AC XY: 5 AN XY: 30795

African (AFR) AF: 0.00 AC: 0 AN: 29412

American (AMR) AF: 0.00 AC: 0 AN: 10047

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2593

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.00 AC: 0 AN: 2545

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000347 AC: 18 AN: 51809

Other (OTH) AF: 0.00 AC: 0 AN: 1434

Alfa AF: 0.00123 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	AP1S2-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.9
DANN	Benign	0.53
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0040
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: rs770199415; hg19: chrX-15863647;