X-15845524-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001272071.2(AP1S2):​c.289-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000065 in 1,077,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000065 (0 hom. 1 hem.)
• Consequence: AP1S2 NM_001272071.2 splice_region, intron
• Scores: Splicing: ADA: 0.0002181
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1S2	NM_001272071.2	c.289-8C>A		splice_region_variant, intron_variant	Intron 3 of 5	ENST00000672987.1	NP_001259000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1S2	ENST00000672987.1	c.289-8C>A		splice_region_variant, intron_variant	Intron 3 of 5		NM_001272071.2	ENSP00000500695.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000650 AC: 7 AN: 1077726 Hom.: 0 Cov.: 32 AF XY: 0.00000284 AC XY: 1 AN XY: 351852

African (AFR) AF: 0.00 AC: 0 AN: 24867

American (AMR) AF: 0.00 AC: 0 AN: 31238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18651

East Asian (EAS) AF: 0.00 AC: 0 AN: 29843

South Asian (SAS) AF: 0.00 AC: 0 AN: 50004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3691

European-Non Finnish (NFE) AF: 0.00000839 AC: 7 AN: 834333

Other (OTH) AF: 0.00 AC: 0 AN: 45090

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.5
DANN	Benign	0.57
PhyloP100		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.032
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;