rs75674611

chr1-244856720-C-Achr1-244856720-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031844.3(HNRNPU):c.1743+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,610,250 control chromosomes in the GnomAD database, including 4 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 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: HNRNPU NM_031844.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001123
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0640

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-244856720-C-A is Benign according to our data. Variant chr1-244856720-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 414106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-244856720-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00282 (429/152326) while in subpopulation AFR AF= 0.00994 (413/41560). AF 95% confidence interval is 0.00915. There are 2 homozygotes in gnomad4. There are 210 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.1743+8G>T		splice_region_variant, intron_variant		ENST00000640218.2
HNRNPU	NM_004501.3	c.1686+8G>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPU	ENST00000640218.2	c.1743+8G>T		splice_region_variant, intron_variant		1	NM_031844.3	P3

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00191

GnomAD3 exomes AF: 0.000638 AC: 158 AN: 247774 Hom.: 0 AF XY: 0.000455 AC XY: 61 AN XY: 133946

Gnomad AFR exome AF: 0.00958

Gnomad AMR exome AF: 0.0000886

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000255 AC: 372 AN: 1457924 Hom.: 2 Cov.: 31 AF XY: 0.000239 AC XY: 173 AN XY: 725122

Gnomad4 AFR exome AF: 0.00931

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000897

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74492

Gnomad4 AFR AF: 0.00994

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00164 Hom.: 2

Bravo AF: 0.00324

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 54 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.28
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0
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: rs75674611; hg19: chr1-245020022;