rs869025343

Variant names:

• chrX-71297938-G-A
• rs869025343
• NM_007363.5:c.1131G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_007363.5(NONO):​c.1131G>A​(p.Ala377Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NONO NM_007363.5 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.53
• 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-71297938-G-A is Pathogenic according to our data. Variant chrX-71297938-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 222081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	NM_007363.5	MANE Select	c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 9 of 12	NP_031389.3
	NONO	NM_001145408.2		c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 10 of 13	NP_001138880.1
	NONO	NM_001145409.2		c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 8 of 11	NP_001138881.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	ENST00000276079.13	TSL:1 MANE Select	c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 9 of 12	ENSP00000276079.8
	NONO	ENST00000373856.8	TSL:1	c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 9 of 13	ENSP00000362963.4
	NONO	ENST00000373841.5	TSL:1	c.1131G>A	p.Ala377Ala	splice_region synonymous	Exon 8 of 11	ENSP00000362947.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1030574 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 305364

African (AFR) AF: 0.00 AC: 0 AN: 25229

American (AMR) AF: 0.00 AC: 0 AN: 34913

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18903

East Asian (EAS) AF: 0.00 AC: 0 AN: 29895

South Asian (SAS) AF: 0.00 AC: 0 AN: 51906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3963

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 781561

Other (OTH) AF: 0.00 AC: 0 AN: 43870

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Syndromic X-linked intellectual disability 34 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Benign	0.94
PhyloP100		3.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.88		Position offset: 0

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

Other links and lift over

dbSNP: rs869025343; hg19: chrX-70517788;