1-244864184-G-T

Variant names:

• chr1-244864184-G-T
• rs1364614921
• NM_031844.3:c.124C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031844.3(HNRNPU):​c.124C>A​(p.Leu42Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,394 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L42P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNRNPU NM_031844.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.66
• Publications: 0 publications found

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

ENSG00000273175 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPU	NM_031844.3	c.124C>A	p.Leu42Met	missense_variant	Exon 1 of 14	ENST00000640218.2	NP_114032.2
HNRNPU	NM_004501.3	c.124C>A	p.Leu42Met	missense_variant	Exon 1 of 14		NP_004492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2	c.124C>A	p.Leu42Met	missense_variant	Exon 1 of 14	1	NM_031844.3	ENSP00000491215.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456394 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724246

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00 AC: 0 AN: 85652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60120

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Uncertain:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 42 of the HNRNPU protein (p.Leu42Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNRNPU-related conditions. ClinVar contains an entry for this variant (Variation ID: 1497414). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L;L;.
PhyloP100		3.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0080	D;.;D
Polyphen		0.87	P;P;.
Vest4		0.41
MutPred		0.57		Gain of catalytic residue at L42 (P = 0.0376);Gain of catalytic residue at L42 (P = 0.0376);Gain of catalytic residue at L42 (P = 0.0376);
MVP		0.66
MPC		1.6
ClinPred		0.83	D
GERP RS		1.2
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.30
gMVP		0.20
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs1364614921; hg19: chr1-245027486;