1-23310756-C-G

Variant names:

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

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>C​(p.Ala534Pro) 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. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A534S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNRNPR NM_005826.5 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.11480588).

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>C	p.Ala534Pro	missense	Exon 11 of 11	NP_005817.1	O43390-1
	HNRNPR	NM_001102398.3		c.1609G>C	p.Ala537Pro	missense	Exon 11 of 11	NP_001095868.1	O43390-2
	HNRNPR	NM_001438564.1		c.1600G>C	p.Ala534Pro	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>C	p.Ala534Pro	missense	Exon 11 of 11	ENSP00000304405.6	O43390-1
	HNRNPR	ENST00000374616.7	TSL:1	c.1609G>C	p.Ala537Pro	missense	Exon 11 of 11	ENSP00000363745.3	O43390-2
	HNRNPR	ENST00000478691.5	TSL:1	c.1306G>C	p.Ala436Pro	missense	Exon 10 of 10	ENSP00000474437.1	O43390-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250800 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461428 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111734

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.22	N
PhyloP100		3.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.031
Sift	Benign	0.40	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.29		Gain of glycosylation at A534 (P = 0.0228)
MVP		0.26
MPC		0.77
ClinPred		0.21	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.69
Mutation Taster		=71/29	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;