rs745485838

Positions:

• chr1-244858803-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_031844.3(HNRNPU):​c.1156A>G​(p.Ile386Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,582,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: HNRNPU NM_031844.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HNRNPU
• BP4: Computational evidence support a benign effect (MetaRNN=0.31010887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPU	NM_031844.3	c.1156A>G	p.Ile386Val	missense_variant	6/14	ENST00000640218.2
HNRNPU	NM_004501.3	c.1099A>G	p.Ile367Val	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2	c.1156A>G	p.Ile386Val	missense_variant	6/14	1	NM_031844.3	P3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152238 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249678 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000377 AC: 54 AN: 1430544 Hom.: 0 Cov.: 25 AF XY: 0.0000378 AC XY: 27 AN XY: 713512

Gnomad4 AFR exome AF: 0.0000913

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000461

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 04, 2023

This variant has not been reported in the literature in individuals affected with HNRNPU-related conditions. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNRNPU protein function. ClinVar contains an entry for this variant (Variation ID: 446392). This variant is present in population databases (rs745485838, gnomAD 0.005%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 386 of the HNRNPU protein (p.Ile386Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.66	N;.;N;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.21	T;.;T;.;.;.;.;.;.
Sift4G	Benign	0.44	T;.;.;.;.;.;.;.;.
Polyphen		0.038	B;B;.;.;.;.;.;.;.
Vest4		0.31
MutPred		0.76		.;Gain of ubiquitination at K384 (P = 0.0641);.;.;.;.;.;.;.;
MVP		0.77
MPC		0.52
ClinPred		0.16	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.31

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

Other links and lift over

dbSNP: rs745485838; hg19: chr1-245022105;