rs1233558404

Positions:

• chr1-244858028-C-G
• chr1-244858028-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000640218.2(HNRNPU):​c.1477G>C​(p.Glu493Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. E493K) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HNRNPU ENST00000640218.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01

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 1 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=0.096735805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPU	NM_031844.3	c.1477G>C	p.Glu493Gln	missense_variant	7/14	ENST00000640218.2	NP_114032.2
HNRNPU	NM_004501.3	c.1420G>C	p.Glu474Gln	missense_variant	7/14		NP_004492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2	c.1477G>C	p.Glu493Gln	missense_variant	7/14	1	NM_031844.3	ENSP00000491215	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74270

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: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.13	.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T;T;T;T;T;T;T;T;D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.097	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;.;.;.;.;.;.
MutationTaster	Benign	0.60	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.0	N;.;.;.;.;.;.;.;.
REVEL	Benign	0.040
Sift	Benign	0.43	T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.34	T;.;.;.;.;.;.;.;.
Polyphen		0.019	B;B;.;.;.;.;.;.;.
Vest4		0.15
MutPred		0.27		.;Loss of ubiquitination at K494 (P = 0.0369);.;.;.;.;.;.;.;
MVP		0.45
MPC		0.62
ClinPred		0.55	D
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.13
gMVP		0.66

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: rs1233558404; hg19: chr1-245021330;