chrX-15827084-T-G
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001272071.2(AP1S2):c.*241A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 397,302 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 0.000011 ( 0 hom. 0 hem. )
Consequence
AP1S2
NM_001272071.2 3_prime_UTR
NM_001272071.2 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.730
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AP1S2 | NM_001272071.2 | c.*241A>C | 3_prime_UTR_variant | 6/6 | ENST00000672987.1 | ||
AP1S2 | NM_003916.5 | c.*241A>C | 3_prime_UTR_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AP1S2 | ENST00000672987.1 | c.*241A>C | 3_prime_UTR_variant | 6/6 | NM_001272071.2 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000268 AC: 3AN: 111814Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33994
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GnomAD4 exome AF: 0.0000105 AC: 3AN: 285488Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 86196
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GnomAD4 genome AF: 0.0000268 AC: 3AN: 111814Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33994
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pettigrew syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The hemizygous c.*241A>C variant in AP1S2 was identified by our study in one individual with developmental delay, developmental regression, self-injurious behavior, mutism, nephrolithiasis, epicanthus, hypermetropia, long ears, hypospadias, pectus excavatum, and structural brain anomalies on MRI. The c.*241A>C variant in AP1S2 has not been previously reported in individuals with Pettigrew syndrome but has been identified in 0.006% (3/53107) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1355982884). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the c.*241A>C variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting (Richards 2015). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at