chr1-244855607-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031844.3(HNRNPU):c.2169C>T(p.Ala723Ala) 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. 3/3 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:6

Conservation

PhyloP100: 1.15

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPU	NM_031844.3 link	c.2169C>T	p.Ala723Ala	splice_region_variant, synonymous_variant	Exon 12 of 14	ENST00000640218.2	NP_114032.2	Q00839-1Q96BA7
HNRNPU	NM_004501.3 link	c.2112C>T	p.Ala704Ala	splice_region_variant, synonymous_variant	Exon 12 of 14		NP_004492.2	Q00839-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPU	ENST00000640218.2 link	c.2169C>T	p.Ala723Ala	splice_region_variant, synonymous_variant	Exon 12 of 14	1	NM_031844.3	ENSP00000491215.1		Q00839-1

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

972

AN:

151974

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00580

AC XY:

786

AN XY:

135590

show subpopulations

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.:

Cov.:

AF XY:

0.00689

AC XY:

5010

AN XY:

727142

show subpopulations

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.:

Cov.:

AF XY:

0.00588

AC XY:

437

AN XY:

74354

show subpopulations

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.:

Bravo

AF:

0.00582

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	HNRNPU: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 26, 2018	- -

Developmental and epileptic encephalopathy, 54

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over