rs1555950011

chrX-71296639-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007363.5(NONO):c.731dup(p.Asn244LysfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NONO NM_007363.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -0.117

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-71296639-T-TA is Pathogenic according to our data. Variant chrX-71296639-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 438778.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NONO	NM_007363.5	c.731dup	p.Asn244LysfsTer21	frameshift_variant	6/12	ENST00000276079.13
NONO	NM_001145408.2	c.731dup	p.Asn244LysfsTer21	frameshift_variant	7/13
NONO	NM_001145409.2	c.731dup	p.Asn244LysfsTer21	frameshift_variant	5/11
NONO	NM_001145410.2	c.464dup	p.Asn155LysfsTer21	frameshift_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NONO	ENST00000276079.13	c.731dup	p.Asn244LysfsTer21	frameshift_variant	6/12	1	NM_007363.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 34 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This frameshifting variant in exon 6 of 12 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has not been previously reported or functionally characterized in the literature to our knowledge. Loss-of-function variation in NONO is a known mechanism of disease for X-linked syndromic intellectual developmental disorder-34 (MRXS34) (PMID: 26571461, 27329731, 27550220, 32397791). The NONO gene is highly constrained (Z-score= 3.59 and pLI = 0.99), which suggests it is intolerant to variation. The c.731dup (p.Asn244LysfsTer21) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.731dup (p.Asn244LysfsTer21) variant is classified as Pathogenic. -

Medulloblastoma Other:1

other, no assertion criteria provided

clinical testing

Donald Williams Parsons Laboratory, Baylor College of Medicine

May 01, 2016

- 3: Mutations in other consensus cancer genes, not currently considered targetable

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: rs1555950011; hg19: chrX-70516489;