rs794729648
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031844.3(HNRNPU):c.2304_2305delAG(p.Gly769fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
HNRNPU
NM_031844.3 frameshift
NM_031844.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.62
Genes affected
HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-244855470-CCT-C is Pathogenic according to our data. Variant chr1-244855470-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNRNPU | NM_031844.3 | c.2304_2305delAG | p.Gly769fs | frameshift_variant | 12/14 | ENST00000640218.2 | NP_114032.2 | |
HNRNPU | NM_004501.3 | c.2247_2248delAG | p.Gly750fs | frameshift_variant | 12/14 | NP_004492.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNRNPU | ENST00000640218.2 | c.2304_2305delAG | p.Gly769fs | frameshift_variant | 12/14 | 1 | NM_031844.3 | ENSP00000491215.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 54 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, University of Torino | Dec 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Intellectual disability and seizures Pathogenic:1
Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 07, 2015 | Mutations in HNRNPU have been reported in patients with intellectual disability and seizures. This gene was first described in a clinical context with respect to the 1q43q44 microdeletion syndrome. The gene content and size of deletions vary among the reported patients, but all patients with a seizure phenotype were missing a copy of HNRNPU, FAM36A and C1orf199 (Baliff et al. 2012, PMID: 21800092). There are now several reports of patients with de novo mutations in HNRNPU who have intellectual disability, developmental delays and, in several cases, seizures (Need et al. 2012, PMID: 22581936; Allen et al. 2013, PMID: 23934111; King et al. 2014, PMID: 24356988; Hamdan et al. 2014, PMID: 25356899). This variant (NM_004051.3:c.2304_2305del) is a likely pathogenic de novo frameshift mutation. This mutation does not occur in the last exon, and may result in a protein with an altered protein composition. This mutation has not previously been reported or observed in a large control database (ExAC). - |
Computational scores
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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