rs794729648

Positions:

• chr1-244855470-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

HNRNPU (HGNC:):

ACMG classification

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, University of Torino	Dec 23, 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

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs794729648; hg19: chr1-245018772;