rs575582638

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1BP6BS1BS2

The NM_031844.3(HNRNPU):c.2166_2167+1delAGG(p.Ala723fs) variant causes a frameshift, splice donor, splice region, intron change. The variant allele was found at a frequency of 0.000713 in 1,613,340 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G722G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 4 hom. )

Consequence

HNRNPU
NM_031844.3 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.78

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 54
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

HNRNPU links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 1-244855902-GCCT-G is Benign according to our data. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563. Variant chr1-244855902-GCCT-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 532563.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000434 (66/152148) while in subpopulation SAS AF = 0.00477 (23/4822). AF 95% confidence interval is 0.00326. There are 1 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPU	NM_031844.3 link	c.2166_2167+1delAGG	p.Ala723fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 11 of 14	ENST00000640218.2	NP_114032.2	Q00839-1Q96BA7
HNRNPU	NM_004501.3 link	c.2109_2110+1delAGG	p.Ala704fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 11 of 14		NP_004492.2	Q00839-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2 link	c.2166_2167+1delAGG	p.Ala723fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 11 of 14	1	NM_031844.3	ENSP00000491215.1		Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00100

AC:

252

AN:

250750

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000555

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000743

AC:

1085

AN:

1461192

Hom.:

AF XY:

0.000880

AC XY:

640

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33420

American (AMR)

AF:

0.000336

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00484

AC:

417

AN:

86152

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000546

AC:

607

AN:

1111668

Other (OTH)

AF:

0.000646

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000434

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41496

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68004

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000172

Hom.:

Bravo

AF:

0.000329

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 54

Uncertain:1Benign:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNRNPU NM_031844.2 exon 11 p.Gly722del (c.2165_2167del): This variant has not been reported in the literature but is present in 0.5% (168/30630) of South Asian alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs575582638). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of 1 amino acid at position 722 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 09, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27048167) -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNRNPU: BS1 -

Inborn genetic diseases

Benign:1

Mar 06, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HNRNPU-related disorder

Benign:1

Jun 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=166/34

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: 5

DS_DL_spliceai

0.99

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over