chr1-244864184-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

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.124C>A	p.Leu42Met	missense	Exon 1 of 14	NP_114032.2	Q00839-1
	HNRNPU	NM_004501.3		c.124C>A	p.Leu42Met	missense	Exon 1 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.124C>A	p.Leu42Met	missense	Exon 1 of 14	ENSP00000491215.1	Q00839-1
	HNRNPU	ENST00000444376.7	TSL:1	c.124C>A	p.Leu42Met	missense	Exon 1 of 14	ENSP00000393151.2	Q00839-2
	HNRNPU	ENST00000919769.1		c.124C>A	p.Leu42Met	missense	Exon 1 of 15	ENSP00000589828.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 54 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.87	P
Vest4		0.41
MutPred		0.57		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;