chr1-244855902-GCCT-G

Variant names:

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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031844.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPU	NM_031844.3	MANE Select	c.2166_2167+1delAGG	p.Ala723fs	frameshift splice_donor splice_region intron	Exon 11 of 14	NP_114032.2	Q00839-1
	HNRNPU	NM_004501.3		c.2109_2110+1delAGG	p.Ala704fs	frameshift splice_donor splice_region intron	Exon 11 of 14	NP_004492.2	Q00839-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPU	ENST00000640218.2	TSL:1 MANE Select	c.2166_2167+1delAGG	p.Ala723fs	frameshift splice_donor splice_region intron	Exon 11 of 14	ENSP00000491215.1	Q00839-1
HNRNPU	ENST00000444376.7	TSL:1	c.2109_2110+1delAGG	p.Ala704fs	frameshift splice_donor splice_region intron	Exon 11 of 14	ENSP00000393151.2	Q00839-2
HNRNPU	ENST00000639628.2	TSL:1	c.1338_1339+1delAGG	p.Ala447fs	frameshift splice_donor splice_region intron	Exon 8 of 11	ENSP00000491340.1	A0A1W2PPH7

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 54 (2)

not provided (2)

HNRNPU-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over