1-244862463-G-A

Position:

chr1-244862463-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM2PP2PP3BP6_Very_StrongBS1

The NM_031844.3(HNRNPU):c.875C>T(p.Thr292Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,566,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

HNRNPU
NM_031844.3 missense, splice_region

Scores

Splicing: ADA: 0.9975

Clinical Significance

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

Conservation

PhyloP100: 8.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 1-244862463-G-A is Benign according to our data. Variant chr1-244862463-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 406727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000402 (57/1418398) while in subpopulation MID AF= 0.000356 (2/5616). AF 95% confidence interval is 0.000234. There are 0 homozygotes in gnomad4_exome. There are 34 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPU	NM_031844.3 linkuse as main transcript	c.875C>T	p.Thr292Ile	missense_variant, splice_region_variant	3/14	ENST00000640218.2
HNRNPU	NM_004501.3 linkuse as main transcript	c.818C>T	p.Thr273Ile	missense_variant, splice_region_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2 linkuse as main transcript	c.875C>T	p.Thr292Ile	missense_variant, splice_region_variant	3/14	1	NM_031844.3	P3	Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.0000405

AC:

AN:

148250

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:

0.00

Gnomad SAS

AF:

0.000428

Gnomad FIN

AF:

0.000106

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000444

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000600

AC:

AN:

250150

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000296

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000402

AC:

AN:

1418398

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

707488

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000329

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000214

Gnomad4 OTH exome

AF:

0.0000511

GnomAD4 genome

AF:

0.0000405

AC:

AN:

148290

Hom.:

Cov.:

AF XY:

0.0000417

AC XY:

AN XY:

72026

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000430

Gnomad4 FIN

AF:

0.000106

Gnomad4 NFE

AF:

0.0000444

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.00

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:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 06, 2020

- -

HNRNPU-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.0044

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.48

T;T;T;T

MetaSVM

Uncertain

-0.047

MutationAssessor

Benign

2.0

.;M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.8

D;.;D;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.0030

D;.;D;.

Sift4G

Uncertain

0.0070

D;.;.;.

Polyphen

0.99

D;D;.;.

Vest4

0.82

MVP

0.70

ClinPred

0.59

GERP RS

5.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.50

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.81

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