rs397515338
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 18P and 1B. PVS1PM2PP5_Very_StrongBS1_Supporting
The ENST00000370552.8(HPSE2):βc.1465_1466delβ(p.Asn489ProfsTer126) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000419 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000370552.8 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HPSE2 | NM_021828.5 | c.1465_1466del | p.Asn489ProfsTer126 | frameshift_variant, splice_region_variant | 10/12 | ENST00000370552.8 | NP_068600.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HPSE2 | ENST00000370552.8 | c.1465_1466del | p.Asn489ProfsTer126 | frameshift_variant, splice_region_variant | 10/12 | 1 | NM_021828.5 | ENSP00000359583 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251464Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135906
GnomAD4 exome AF: 0.000445 AC: 650AN: 1461836Hom.: 0 AF XY: 0.000422 AC XY: 307AN XY: 727210
GnomAD4 genome AF: 0.000177 AC: 27AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74482
ClinVar
Submissions by phenotype
Urofacial syndrome type 1 Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 11, 2019 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins-Biomnis | Dec 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 17, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 22, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 11, 2010 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2023 | Frameshift variant predicted to result in the deletion of the last 104 amino acids, replaced with 125 incorrect amino acids; This variant is associated with the following publications: (PMID: 20560209, 11446407, 31589614, 35812751, 20560210) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 21, 2023 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 84). This premature translational stop signal has been observed in individuals with urofacial syndrome (PMID: 20560209, 20560210). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs397515338, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Asn489Profs*126) in the HPSE2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 104 amino acid(s) of the HPSE2 protein. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at