1-23310548-G-A

Variant names:

• chr1-23310548-G-A
• rs1645289441
• NM_005826.5:c.1808C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005826.5(HNRNPR):​c.1808C>T​(p.Pro603Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HNRNPR NM_005826.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

Genes affected

HNRNPR (HGNC:5047): (heterogeneous nuclear ribonucleoprotein R) This gene encodes an RNA-binding protein that is a member of the spliceosome C complex, which functions in pre-mRNA processing and transport. The encoded protein also promotes transcription at the c-fos gene. Alternative splicing results in multiple transcript variants. There are pseudogenes for this gene on chromosomes 4, 11, and 10. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPR	NM_005826.5	c.1808C>T	p.Pro603Leu	missense_variant	Exon 11 of 11	ENST00000302271.11	NP_005817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPR	ENST00000302271.11	c.1808C>T	p.Pro603Leu	missense_variant	Exon 11 of 11	1	NM_005826.5	ENSP00000304405.6
HNRNPR	ENST00000374616.7	c.1817C>T	p.Pro606Leu	missense_variant	Exon 11 of 11	1		ENSP00000363745.3
HNRNPR	ENST00000478691.5	c.1514C>T	p.Pro505Leu	missense_variant	Exon 10 of 10	1		ENSP00000474437.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

HNRNPR-related disorder Uncertain:1

Aug 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HNRNPR c.1817C>T variant is predicted to result in the amino acid substitution p.Pro606Leu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;.;D;D;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	.;.;M;M;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	.;D;D;D;.;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	.;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;.
Vest4		0.63
MutPred		0.32		.;.;Gain of stability (P = 0.0053);Gain of stability (P = 0.0053);.;.;
MVP		0.67
MPC		0.61
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.81

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: rs1645289441; hg19: chr1-23637041;