1-23310712-A-AC

Variant names:

• chr1-23310712-A-AC
• NM_005826.5:c.1643dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005826.5(HNRNPR):​c.1643dupG​(p.Pro549SerfsTer34) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPR NM_005826.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.92
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-23310712-A-AC is Pathogenic according to our data. Variant chr1-23310712-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 1710308.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1643dupG	p.Pro549SerfsTer34	frameshift	Exon 11 of 11	NP_005817.1	O43390-1
	HNRNPR	NM_001102398.3		c.1652dupG	p.Pro552SerfsTer34	frameshift	Exon 11 of 11	NP_001095868.1	O43390-2
	HNRNPR	NM_001438564.1		c.1643dupG	p.Pro549SerfsTer34	frameshift	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.1643dupG	p.Pro549SerfsTer34	frameshift	Exon 11 of 11	ENSP00000304405.6	O43390-1
	HNRNPR	ENST00000374616.7	TSL:1	c.1652dupG	p.Pro552SerfsTer34	frameshift	Exon 11 of 11	ENSP00000363745.3	O43390-2
	HNRNPR	ENST00000478691.5	TSL:1	c.1349dupG	p.Pro451SerfsTer34	frameshift	Exon 10 of 10	ENSP00000474437.1	O43390-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=0/200	disease causing

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

hg19: chr1-23637205;