Genetic Variant HNRNPU:p.Glu87Asp (chr1-244864047-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031844.3(HNRNPU):c.261G>C(p.Glu87Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E87E) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HNRNPU
NM_031844.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.468

Publications

0 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:

ENSG00000273175 (HGNC:):

ENSG00000273175 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054892898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPU	NM_031844.3 link	c.261G>C	p.Glu87Asp	missense_variant	Exon 1 of 14	ENST00000640218.2	NP_114032.2	Q00839-1Q96BA7
HNRNPU	NM_004501.3 link	c.261G>C	p.Glu87Asp	missense_variant	Exon 1 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.261G>C	p.Glu87Asp	missense_variant	Exon 1 of 14	1	NM_031844.3	ENSP00000491215.1		Q00839-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456606

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.00

AC:

AN:

44066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39478

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109736

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.10

.;T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.055

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.;.

PhyloP100

-0.47

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.25

N;.;N;.

REVEL

Benign

0.031

Sift

Benign

0.88

T;.;T;.

Sift4G

Benign

0.59

T;.;T;.

Polyphen

0.072

B;B;.;.

Vest4

0.11

MutPred

0.42

Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;

MVP

0.40

MPC

0.75

ClinPred

0.080

GERP RS

2.8

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.081

gMVP

0.050

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over