X-71290791-AGT-A

Variant names:

• chrX-71290791-AGT-A
• NM_007363.5:c.154+5_154+6delGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_007363.5(NONO):​c.154+5_154+6delGT variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NONO NM_007363.5 splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.70
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-71290791-AGT-A is Pathogenic according to our data. Variant chrX-71290791-AGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1704653.Status of the report is no_assertion_criteria_provided, 0 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.154+5_154+6delGT		splice_region intron	N/A	NP_031389.3
	NONO	NM_001145408.2		c.154+5_154+6delGT		splice_region intron	N/A	NP_001138880.1	A0A0S2Z4Z9
	NONO	NM_001145409.2		c.154+5_154+6delGT		splice_region intron	N/A	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.154+5_154+6delGT		splice_region intron	N/A	ENSP00000276079.8	Q15233-1
	NONO	ENST00000373856.8	TSL:1	c.154+5_154+6delGT		splice_region intron	N/A	ENSP00000362963.4	A0A7P0MRW0
	NONO	ENST00000373841.5	TSL:1	c.154+5_154+6delGT		splice_region intron	N/A	ENSP00000362947.1	Q15233-1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Syndromic X-linked intellectual disability 34 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: 4
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chrX-70510641;