NM_031844.3:c.651_660delAGGCGGCGGA

Variant names:

• chr1-244863647-CTCCGCCGCCT-C
• rs779453109
• NM_031844.3:c.651_660delAGGCGGCGGA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 9P and 5B. PVS1 PP5 BS1_Supporting BS2

The NM_031844.3(HNRNPU):​c.651_660delAGGCGGCGGA​(p.Gly218AlafsTer118) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,552,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: HNRNPU NM_031844.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 3.36
• Publications: 3 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 4 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-244863647-CTCCGCCGCCT-C is Pathogenic according to our data. Variant chr1-244863647-CTCCGCCGCCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 267738.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000025 (35/1400306) while in subpopulation MID AF = 0.000231 (1/4338). AF 95% confidence interval is 0.0000386. There are 0 homozygotes in GnomAdExome4. There are 24 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 35 AD gene.

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.651_660delAGGCGGCGGA	p.Gly218AlafsTer118	frameshift	Exon 1 of 14	NP_114032.2	Q00839-1
	HNRNPU	NM_004501.3		c.634+17_634+26delAGGCGGCGGA		intron	N/A	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.651_660delAGGCGGCGGA	p.Gly218AlafsTer118	frameshift	Exon 1 of 14	ENSP00000491215.1	Q00839-1
	HNRNPU	ENST00000444376.7	TSL:1	c.634+17_634+26delAGGCGGCGGA		intron	N/A	ENSP00000393151.2	Q00839-2
	HNRNPU	ENST00000919769.1		c.651_660delAGGCGGCGGA	p.Gly218AlafsTer118	frameshift	Exon 1 of 15	ENSP00000589828.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD2 exomes AF: 0.0000118 AC: 2 AN: 169072 AF XY: 0.0000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000893

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 35 AN: 1400306 Hom.: 0 AF XY: 0.0000345 AC XY: 24 AN XY: 696410

African (AFR) AF: 0.0000348 AC: 1 AN: 28698

American (AMR) AF: 0.0000266 AC: 1 AN: 37654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.000114 AC: 4 AN: 34986

South Asian (SAS) AF: 0.00 AC: 0 AN: 81516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36956

Middle Eastern (MID) AF: 0.000231 AC: 1 AN: 4338

European-Non Finnish (NFE) AF: 0.0000247 AC: 27 AN: 1094004

Other (OTH) AF: 0.0000173 AC: 1 AN: 57970

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74156

African (AFR) AF: 0.0000483 AC: 2 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Developmental and epileptic encephalopathy, 54 (4)
1	-	-	Epileptic encephalopathy (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779453109; hg19: chr1-245026949;