chr1-244854505-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_031844.3(HNRNPU):​c.2425-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

HNRNPU
NM_031844.3 splice_acceptor, intron

Scores

4
1
2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 4.05
Variant links:
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-244854505-T-C is Pathogenic according to our data. Variant chr1-244854505-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 559858.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
HNRNPUNM_031844.3 linkc.2425-2A>G splice_acceptor_variant, intron_variant ENST00000640218.2 NP_114032.2 Q00839-1Q96BA7
HNRNPUNM_004501.3 linkc.2368-2A>G splice_acceptor_variant, intron_variant NP_004492.2 Q00839-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HNRNPUENST00000640218.2 linkc.2425-2A>G splice_acceptor_variant, intron_variant 1 NM_031844.3 ENSP00000491215.1 Q00839-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneAug 04, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 07, 2024Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33874999, 38846959, 35138025) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
34
DANN
Benign
0.95
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
GERP RS
6.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.87
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.98
Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553281924; hg19: chr1-245017807; API