rs779453109
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_031844.3(HNRNPU):c.651_660delAGGCGGCGGA(p.Gly218AlafsTer118) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,552,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_031844.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNRNPU | NM_031844.3 | c.651_660delAGGCGGCGGA | p.Gly218AlafsTer118 | frameshift_variant | Exon 1 of 14 | ENST00000640218.2 | NP_114032.2 | |
HNRNPU | NM_004501.3 | c.634+17_634+26delAGGCGGCGGA | intron_variant | Intron 1 of 13 | NP_004492.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151844Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000118 AC: 2AN: 169072Hom.: 0 AF XY: 0.0000104 AC XY: 1AN XY: 96484
GnomAD4 exome AF: 0.0000250 AC: 35AN: 1400306Hom.: 0 AF XY: 0.0000345 AC XY: 24AN XY: 696410
GnomAD4 genome AF: 0.0000198 AC: 3AN: 151844Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74156
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 54 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 15, 2024 | This sequence change creates a premature translational stop signal (p.Gly218Alafs*118) in the HNRNPU gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNRNPU are known to be pathogenic (PMID: 22678713, 28283832). This variant is present in population databases (rs779453109, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with HNRNPU-related conditions (PMID: 28815871). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 267738). For these reasons, this variant has been classified as Pathogenic. - |
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 26, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 16, 2025 | De novo variant with confirmed parentage in a patient with developmental delay and regression, congenital hypotonia, seizures, hippocampal malrotation, and macrocephaly (PMID: 28815871); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 28815871, 34312540, 37776660) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at