rs760669739

Positions:

chr1-244858237-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM2PP2BP4_ModerateBP6_Very_StrongBS1

The NM_031844.3(HNRNPU):c.1268A>G(p.Lys423Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K423Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

HNRNPU
NM_031844.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.97

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:

HNRNPU (HGNC:):

HNRNPU links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 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=0.113770366).

BP6

Variant 1-244858237-T-C is Benign according to our data. Variant chr1-244858237-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 414099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-244858237-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000591 (9/152252) while in subpopulation EAS AF= 0.00173 (9/5206). AF 95% confidence interval is 0.000901. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1268A>G	p.Lys423Arg	missense_variant	7/14	ENST00000640218.2	NP_114032.2	Q00839-1Q96BA7
HNRNPU	NM_004501.3 linkuse as main transcript	c.1211A>G	p.Lys404Arg	missense_variant	7/14		NP_004492.2	Q00839-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2 linkuse as main transcript	c.1268A>G	p.Lys423Arg	missense_variant	7/14	1	NM_031844.3	ENSP00000491215.1		Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000203

AC:

AN:

251346

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00277

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 54

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2023	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

.;D;T;.;.;.;.;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.037

MutationAssessor

Uncertain

2.5

.;M;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

D;.;D;.;.;.;.;.;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0070

D;.;D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.;.;.;.;.

Polyphen

1.0

D;D;.;.;.;.;.;.;.

Vest4

0.92

MVP

0.94

MPC

0.51

ClinPred

0.17

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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