1-244858071-G-C

Variant names:

• chr1-244858071-G-C
• rs778730784
• NM_031844.3:c.1434C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031844.3(HNRNPU):​c.1434C>G​(p.Asn478Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N478S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNRNPU NM_031844.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 2 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15319082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031844.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPU	NM_031844.3	MANE Select	c.1434C>G	p.Asn478Lys	missense	Exon 7 of 14	NP_114032.2	Q00839-1
	HNRNPU	NM_004501.3		c.1377C>G	p.Asn459Lys	missense	Exon 7 of 14	NP_004492.2	Q00839-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPU	ENST00000640218.2	TSL:1 MANE Select	c.1434C>G	p.Asn478Lys	missense	Exon 7 of 14	ENSP00000491215.1	Q00839-1
	HNRNPU	ENST00000444376.7	TSL:1	c.1377C>G	p.Asn459Lys	missense	Exon 7 of 14	ENSP00000393151.2	Q00839-2
	HNRNPU	ENST00000639628.2	TSL:1	c.606C>G	p.Asn202Lys	missense	Exon 4 of 11	ENSP00000491340.1	A0A1W2PPH7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251404 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461730 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.38	N
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.078
Sift	Benign	0.27	T
Sift4G	Benign	0.33	T
Polyphen		0.35	B
Vest4		0.25
MutPred		0.48		Gain of methylation at N478 (P = 0.0016)
MVP		0.36
MPC		0.72
ClinPred		0.14	T
GERP RS		-0.58
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.56
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778730784; hg19: chr1-245021373;