rs11537737

chr1-244855607-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031844.3(HNRNPU):c.2169C>T(p.Ala723=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0069 in 1,613,750 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (46 hom.)
• Consequence: HNRNPU NM_031844.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003392
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.15

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-244855607-G-A is Benign according to our data. Variant chr1-244855607-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 414105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-244855607-G-A is described in Lovd as [Likely_benign]. Variant chr1-244855607-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0064 (973/152092) while in subpopulation NFE AF= 0.0101 (686/67974). AF 95% confidence interval is 0.00947. There are 2 homozygotes in gnomad4. There are 437 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPU	NM_031844.3	c.2169C>T	p.Ala723=	splice_region_variant, synonymous_variant	12/14	ENST00000640218.2
HNRNPU	NM_004501.3	c.2112C>T	p.Ala704=	splice_region_variant, synonymous_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2	c.2169C>T	p.Ala723=	splice_region_variant, synonymous_variant	12/14	1	NM_031844.3	P3

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 972 AN: 151974 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00577 AC: 1448 AN: 250808 Hom.: 11 AF XY: 0.00580 AC XY: 786 AN XY: 135590

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00886

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.00858

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00695 AC: 10165 AN: 1461658 Hom.: 46 Cov.: 31 AF XY: 0.00689 AC XY: 5010 AN XY: 727142

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00471

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.00803

Gnomad4 OTH exome AF: 0.00758

GnomAD4 genome AF: 0.00640 AC: 973 AN: 152092 Hom.: 2 Cov.: 32 AF XY: 0.00588 AC XY: 437 AN XY: 74354

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.00557

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00870

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00882 Hom.: 13

Bravo AF: 0.00582

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HNRNPU: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Developmental and epileptic encephalopathy, 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	11
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0020
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: rs11537737; hg19: chr1-245018909; COSMIC: COSV51689682; COSMIC: COSV51689682;