rs869025344

Variant names:

• chrX-71300050-G-GC
• rs869025344
• NM_007363.5:c.1394dupC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_007363.5(NONO):​c.1394dupC​(p.Asn466LysfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001480234: Immunoblot and immunocytochemistry studies using skin fibroblasts from an affected male demonstrated that the p.Asn466LysfsTer13 variant results in nearly undetectable levels of NONO [PMID:26571461].".

• Frequency: Genomes: not found (cov: 22)
• Consequence: NONO NM_007363.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.50
• Publications: 4 publications found

Genes affected

NONO (HGNC:7871): (non-POU domain containing octamer binding) This gene encodes an RNA-binding protein which plays various roles in the nucleus, including transcriptional regulation and RNA splicing. A rearrangement between this gene and the transcription factor E3 gene has been observed in papillary renal cell carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes exist on Chromosomes 2 and 16. [provided by RefSeq, Feb 2009]

NONO Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• syndromic X-linked intellectual disability 34

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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. Fraction of 0.0148 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001480234: Immunoblot and immunocytochemistry studies using skin fibroblasts from an affected male demonstrated that the p.Asn466LysfsTer13 variant results in nearly undetectable levels of NONO [PMID: 26571461].
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71300050-G-GC is Pathogenic according to our data. Variant chrX-71300050-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 222082.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007363.5. 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
	NONO	NM_007363.5	MANE Select	c.1394dupC	p.Asn466LysfsTer13	frameshift	Exon 12 of 12	NP_031389.3
	NONO	NM_001145408.2		c.1394dupC	p.Asn466LysfsTer13	frameshift	Exon 13 of 13	NP_001138880.1	A0A0S2Z4Z9
	NONO	NM_001145409.2		c.1394dupC	p.Asn466LysfsTer13	frameshift	Exon 11 of 11	NP_001138881.1	Q15233-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	ENST00000276079.13	TSL:1 MANE Select	c.1394dupC	p.Asn466LysfsTer13	frameshift	Exon 12 of 12	ENSP00000276079.8	Q15233-1
	NONO	ENST00000373856.8	TSL:1	c.1492dupC	p.Gln498ProfsTer8	frameshift	Exon 13 of 13	ENSP00000362963.4	A0A7P0MRW0
	NONO	ENST00000373841.5	TSL:1	c.1394dupC	p.Asn466LysfsTer13	frameshift	Exon 11 of 11	ENSP00000362947.1	Q15233-1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Syndromic X-linked intellectual disability 34 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs869025344;

hg19: chrX-70519900;