chr1-23310756-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• Publications: 1 publications found

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]

HNRNPR Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005826.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPR	NM_005826.5	MANE Select	c.1600G>T	p.Ala534Ser	missense	Exon 11 of 11	NP_005817.1	O43390-1
	HNRNPR	NM_001102398.3		c.1609G>T	p.Ala537Ser	missense	Exon 11 of 11	NP_001095868.1	O43390-2
	HNRNPR	NM_001438564.1		c.1600G>T	p.Ala534Ser	missense	Exon 11 of 11	NP_001425493.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPR	ENST00000302271.11	TSL:1 MANE Select	c.1600G>T	p.Ala534Ser	missense	Exon 11 of 11	ENSP00000304405.6	O43390-1
	HNRNPR	ENST00000374616.7	TSL:1	c.1609G>T	p.Ala537Ser	missense	Exon 11 of 11	ENSP00000363745.3	O43390-2
	HNRNPR	ENST00000478691.5	TSL:1	c.1306G>T	p.Ala436Ser	missense	Exon 10 of 10	ENSP00000474437.1	O43390-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250800 AF XY: 0.00

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 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PhyloP100		3.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.026
Sift	Benign	0.43	T
Sift4G	Benign	0.67	T
Polyphen		0.0050	B
Vest4		0.11
MutPred		0.25		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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs761005559; hg19: chr1-23637249;