1-23310756-C-A

Variant names:

• chr1-23310756-C-A
• rs761005559
• NM_005826.5:c.1600G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005826.5(HNRNPR):​c.1600G>T​(p.Ala534Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPR NM_005826.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09617829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPR	NM_005826.5	c.1600G>T	p.Ala534Ser	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.1600G>T	p.Ala534Ser	missense_variant	Exon 11 of 11	1	NM_005826.5	ENSP00000304405.6
HNRNPR	ENST00000374616.7	c.1609G>T	p.Ala537Ser	missense_variant	Exon 11 of 11	1		ENSP00000363745.3
HNRNPR	ENST00000478691.5	c.1306G>T	p.Ala436Ser	missense_variant	Exon 10 of 10	1		ENSP00000474437.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250800 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1609G>T (p.A537S) alteration is located in coding exon 10 of the HNRNPR gene. This alteration results from a G to T substitution at nucleotide position 1609, causing the alanine (A) at amino acid position 537 to be replaced by a serine (S). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.12	.;.;T;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.033
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.096	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	.;.;N;N;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.10	.;N;N;N;.;N
REVEL	Benign	0.026
Sift	Benign	0.43	.;T;T;T;.;T
Sift4G	Benign	0.67	T;T;T;T;T;T
Polyphen		0.0050, 0.0030, 0.0	.;B;B;B;B;.
Vest4		0.11
MutPred		0.25		.;.;Gain of phosphorylation at A534 (P = 0.0013);Gain of phosphorylation at A534 (P = 0.0013);.;.;
MVP		0.29
MPC		0.54
ClinPred		0.30	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.46

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: rs761005559; hg19: chr1-23637249;