rs6675421

Positions:

• chr1-244864047-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_031844.3(HNRNPU):​c.261G>A​(p.Glu87=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,608,226 control chromosomes in the GnomAD database, including 50,356 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6618 hom., cov: 33)
  • Exomes 𝑓: 0.24 (43738 hom.)
• Consequence: HNRNPU NM_031844.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.468

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-244864047-C-T is Benign according to our data. Variant chr1-244864047-C-T is described in ClinVar as [Benign]. Clinvar id is 586025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.468 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPU	NM_031844.3	c.261G>A	p.Glu87=	synonymous_variant	1/14	ENST00000640218.2	NP_114032.2
HNRNPU	NM_004501.3	c.261G>A	p.Glu87=	synonymous_variant	1/14		NP_004492.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2	c.261G>A	p.Glu87=	synonymous_variant	1/14	1	NM_031844.3	ENSP00000491215	P3
	ENST00000610145.2	n.266C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 43049 AN: 151940 Hom.: 6601 Cov.: 33

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.262

GnomAD3 exomes AF: 0.271 AC: 63556 AN: 234182 Hom.: 9424 AF XY: 0.261 AC XY: 33444 AN XY: 128260

Gnomad AFR exome AF: 0.374

Gnomad AMR exome AF: 0.431

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.183

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.225

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.239 AC: 348360 AN: 1456170 Hom.: 43738 Cov.: 37 AF XY: 0.237 AC XY: 171824 AN XY: 724006

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.422

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.241

GnomAD4 genome AF: 0.283 AC: 43090 AN: 152056 Hom.: 6618 Cov.: 33 AF XY: 0.287 AC XY: 21342 AN XY: 74292

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.259

Alfa AF: 0.240 Hom.: 1329

Bravo AF: 0.290

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Developmental and epileptic encephalopathy, 54 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.97

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: rs6675421; hg19: chr1-245027349; COSMIC: COSV51690210; COSMIC: COSV51690210;