rs869025344

Positions:

• chrX-71300050-G-GC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_007363.5(NONO):​c.1394dupC​(p.Asn466fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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 0 pathogenic variants in the truncated region.
• 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 id is 222082.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.1394dupC	p.Asn466fs	frameshift_variant	12/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.1394dupC	p.Asn466fs	frameshift_variant	13/13		NP_001138880.1
NONO	NM_001145409.2	c.1394dupC	p.Asn466fs	frameshift_variant	11/11		NP_001138881.1
NONO	NM_001145410.2	c.1127dupC	p.Asn377fs	frameshift_variant	10/10		NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.1394dupC	p.Asn466fs	frameshift_variant	12/12	1	NM_007363.5	ENSP00000276079.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 34 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 28, 2019	The de novo c.1394dup (p.Asn466LysfsTer13) variant identified in the NONO gene leads to a frameshift of the protein at amino acid 466/472 (coding exon 11/11). This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. It is reported in ClinVar as Pathogenic (VarID:222082) based on literature evidence. The c.1394dup (p.Asn466LysfsTer13) variant has been reported in two affected individuals in the literature [PMID: 27550220; PMID: 26571461] including a 5y male with hypotonia, global developmental delay, dysmorphic features and left ventricular non-compaction [PMID: 27550220]. 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]. Given the presence of this variant in 2 affected individuals in the literature, its absence in population databases, its presence de novo in this individual, and near absence of NONO protein in fibroblasts of a patient reported in the literature, the c.1394dup (p.Asn466LysfsTer13) variant identified in this individual is reported here as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2021	- -

Computational scores

Source: dbNSFP v4.3

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: rs869025344; hg19: chrX-70519900;