rs199740131

chr1-244858045-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS1

The NM_031844.3(HNRNPU):c.1460G>C(p.Gly487Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,398 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (2 hom.)
• Consequence: HNRNPU NM_031844.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.93

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HNRNPU
• BP4: Computational evidence support a benign effect (MetaRNN=0.021663368).
• BP6: Variant 1-244858045-C-G is Benign according to our data. Variant chr1-244858045-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 406729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/151684) while in subpopulation EAS AF= 0.00213 (11/5162). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPU	NM_031844.3	c.1460G>C	p.Gly487Ala	missense_variant	7/14	ENST00000640218.2
HNRNPU	NM_004501.3	c.1403G>C	p.Gly468Ala	missense_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2	c.1460G>C	p.Gly487Ala	missense_variant	7/14	1	NM_031844.3	P3

Frequencies

GnomAD3 genomes AF: 0.000139 AC: 21 AN: 151596 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000916 AC: 23 AN: 251114 Hom.: 1 AF XY: 0.0000810 AC XY: 11 AN XY: 135744

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461714 Hom.: 2 Cov.: 33 AF XY: 0.0000303 AC XY: 22 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000138 AC: 21 AN: 151684 Hom.: 0 Cov.: 33 AF XY: 0.000149 AC XY: 11 AN XY: 74064

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	HNRNPU: PP2, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2020	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2019

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. -

Developmental and epileptic encephalopathy, 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.15	T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.095	T;.;.;.;.;.;.;.;.
Polyphen		0.92	P;D;.;.;.;.;.;.;.
Vest4		0.64
MVP		0.77
MPC		0.67
ClinPred		0.079	T
GERP RS		5.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.47
gMVP		0.89

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: rs199740131; hg19: chr1-245021347;