Variant 1-244863647-CTCCGCCGCCT-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_031844.3(HNRNPU):c.651_660del(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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

HNRNPU
NM_031844.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.36

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]

HNRNPU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 1-244863647-CTCCGCCGCCT-C is Pathogenic according to our data. Variant chr1-244863647-CTCCGCCGCCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 267738.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1}. Variant chr1-244863647-CTCCGCCGCCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPU	NM_031844.3 linkuse as main transcript	c.651_660del	p.Gly218AlafsTer118	frameshift_variant	1/14	ENST00000640218.2
HNRNPU	NM_004501.3 linkuse as main transcript	c.634+17_634+26del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2 linkuse as main transcript	c.651_660del	p.Gly218AlafsTer118	frameshift_variant	1/14	1	NM_031844.3	P3	Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151844

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000118

AC:

AN:

169072

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

96484

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000893

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000250

AC:

AN:

1400306

Hom.:

AF XY:

0.0000345

AC XY:

AN XY:

696410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000348

Gnomad4 AMR exome

AF:

0.0000266

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000114

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000247

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 54

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 18, 2023	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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 267738). 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. This variant is present in population databases (rs779453109, gnomAD 0.008%). -
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	- -

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

Mar 08, 2022

De novo variant with confirmed parentage in a patient with developmental delay and regression, congenital hypotonia, seizures, hippocampal malrotation, and macrocephaly (Leduc et al., 2017); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28815871, 31589614) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over