rs200952460

Positions:

chr1-244864225-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM2PP2BP4_StrongBP6_Very_StrongBS1

The ENST00000640218.2(HNRNPU):c.83A>G(p.Lys28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,612,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

HNRNPU
ENST00000640218.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.46

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HNRNPU. . Gene score misZ 3.3718 (greater than the threshold 3.09). Trascript score misZ 3.5021 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 54, complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.014719665).

BP6

Variant 1-244864225-T-C is Benign according to our data. Variant chr1-244864225-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 446406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000158 (24/152328) while in subpopulation EAS AF= 0.00135 (7/5180). AF 95% confidence interval is 0.000634. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPU	NM_031844.3 linkuse as main transcript	c.83A>G	p.Lys28Arg	missense_variant	1/14	ENST00000640218.2	NP_114032.2
HNRNPU	NM_004501.3 linkuse as main transcript	c.83A>G	p.Lys28Arg	missense_variant	1/14		NP_004492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2 linkuse as main transcript	c.83A>G	p.Lys28Arg	missense_variant	1/14	1	NM_031844.3	ENSP00000491215	P3	Q00839-1
	ENST00000610145.2 linkuse as main transcript	n.444T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000154

AC:

AN:

245976

Hom.:

AF XY:

0.000156

AC XY:

AN XY:

134202

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00107

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1460586

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

726588

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000219

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000158

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000190

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

HNRNPU: PP2, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.88

DEOGEN2

Benign

0.12

.;T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.17

N;.;N

REVEL

Benign

0.080

Sift

Benign

0.68

T;.;T

Sift4G

Benign

0.56

T;.;T

Polyphen

0.27

B;P;.

Vest4

0.14

MVP

0.54

MPC

1.4

ClinPred

0.049

GERP RS

4.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.096

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over