rs779453109

Positions:

• chr1-244863647-CTCCGCCGCCT-C
• chr1-244863647-CTCCGCCGCCT-CTCCGCCGCCTTCCGCCGCCT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 3.36

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]

ACMG classification

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: {Uncertain_significance=1, Pathogenic=4}. Variant chr1-244863647-CTCCGCCGCCT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPU	NM_031844.3	c.651_660del	p.Gly218AlafsTer118	frameshift_variant	1/14	ENST00000640218.2	NP_114032.2
HNRNPU	NM_004501.3	c.634+17_634+26del		intron_variant			NP_004492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2	c.651_660del	p.Gly218AlafsTer118	frameshift_variant	1/14	1	NM_031844.3	ENSP00000491215	P3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151844 Hom.: 0 Cov.: 32

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: 2 AN: 169072 Hom.: 0 AF XY: 0.0000104 AC XY: 1 AN XY: 96484

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: 35 AN: 1400306 Hom.: 0 AF XY: 0.0000345 AC XY: 24 AN XY: 696410

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: 3 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74156

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.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs779453109; hg19: chr1-245026949;