rs11537737

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031844.3(HNRNPU):c.2169C>T(p.Ala723Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,613,750 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 46 hom. )

Consequence

HNRNPU
NM_031844.3 splice_region, synonymous

Scores

Splicing: ADA: 0.00003392

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.15

Publications

4 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 1-244855607-G-A is Benign according to our data. Variant chr1-244855607-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.15 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0064 (973/152092) while in subpopulation NFE AF = 0.0101 (686/67974). AF 95% confidence interval is 0.00947. There are 2 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 973 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPU	NM_031844.3 link	c.2169C>T	p.Ala723Ala	splice_region_variant, synonymous_variant	Exon 12 of 14	ENST00000640218.2	NP_114032.2	Q00839-1Q96BA7
HNRNPU	NM_004501.3 link	c.2112C>T	p.Ala704Ala	splice_region_variant, synonymous_variant	Exon 12 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.2169C>T	p.Ala723Ala	splice_region_variant, synonymous_variant	Exon 12 of 14	1	NM_031844.3	ENSP00000491215.1		Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

972

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00227

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00868

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.00577

AC:

1448

AN:

250808

AF XY:

0.00580

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00319

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00886

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.00858

Gnomad OTH exome

AF:

0.00654

GnomAD4 exome

AF:

0.00695

AC:

10165

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

5010

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

33462

American (AMR)

AF:

0.00342

AC:

153

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26122

East Asian (EAS)

AF:

0.00471

AC:

187

AN:

39696

South Asian (SAS)

AF:

0.00143

AC:

123

AN:

86254

European-Finnish (FIN)

AF:

0.00419

AC:

224

AN:

53402

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00803

AC:

8930

AN:

1111860

Other (OTH)

AF:

0.00758

AC:

458

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

487

974

1462

1949

2436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00640

AC:

973

AN:

152092

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

437

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

41492

American (AMR)

AF:

0.00557

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00870

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0101

AC:

686

AN:

67974

Other (OTH)

AF:

0.0114

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00832

Hom.:

Bravo

AF:

0.00582

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 26, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HNRNPU: BP4, BP7, BS2 -

Inborn genetic diseases

Benign:1

Dec 23, 2016

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. -

Developmental and epileptic encephalopathy, 54

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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