rs141449330
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM2PP2PP3BP6_Very_StrongBS1
The NM_031844.3(HNRNPU):c.875C>T(p.Thr292Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,566,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
HNRNPU
NM_031844.3 missense, splice_region
NM_031844.3 missense, splice_region
Scores
4
10
3
Splicing: ADA: 0.9975
2
Clinical Significance
Conservation
PhyloP100: 8.05
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 Benign. Variant got -8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HNRNPU
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
BP6
?
Variant 1-244862463-G-A is Benign according to our data. Variant chr1-244862463-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 406727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000402 (57/1418398) while in subpopulation MID AF= 0.000356 (2/5616). AF 95% confidence interval is 0.000234. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNRNPU | NM_031844.3 | c.875C>T | p.Thr292Ile | missense_variant, splice_region_variant | 3/14 | ENST00000640218.2 | |
HNRNPU | NM_004501.3 | c.818C>T | p.Thr273Ile | missense_variant, splice_region_variant | 3/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNRNPU | ENST00000640218.2 | c.875C>T | p.Thr292Ile | missense_variant, splice_region_variant | 3/14 | 1 | NM_031844.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000405 AC: 6AN: 148250Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000600 AC: 15AN: 250150Hom.: 0 AF XY: 0.0000961 AC XY: 13AN XY: 135234
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GnomAD4 exome AF: 0.0000402 AC: 57AN: 1418398Hom.: 0 Cov.: 30 AF XY: 0.0000481 AC XY: 34AN XY: 707488
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GnomAD4 genome ? AF: 0.0000405 AC: 6AN: 148290Hom.: 0 Cov.: 32 AF XY: 0.0000417 AC XY: 3AN XY: 72026
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 54 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2020 | - - |
HNRNPU-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 11, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;.
REVEL
Uncertain
Sift
Uncertain
D;.;D;.
Sift4G
Uncertain
D;.;.;.
Polyphen
D;D;.;.
Vest4
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at