rs1114167441

Variant names:

• chrX-71298508-G-T
• rs1114167441
• NM_007363.5:c.1171G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_007363.5(NONO):​c.1171G>T​(p.Gly391Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G391S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NONO NM_007363.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.92
• Publications: 1 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: Likely_pathogenic. The variant received 7 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-71298508-G-T is Pathogenic according to our data. Variant chrX-71298508-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 427778.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.1171G>T	p.Gly391Cys	missense splice_region	Exon 10 of 12	NP_031389.3
	NONO	NM_001145408.2		c.1171G>T	p.Gly391Cys	missense splice_region	Exon 11 of 13	NP_001138880.1
	NONO	NM_001145409.2		c.1171G>T	p.Gly391Cys	missense splice_region	Exon 9 of 11	NP_001138881.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	ENST00000276079.13	TSL:1 MANE Select	c.1171G>T	p.Gly391Cys	missense splice_region	Exon 10 of 12	ENSP00000276079.8
	NONO	ENST00000373856.8	TSL:1	c.1171G>T	p.Gly391Cys	missense splice_region	Exon 10 of 13	ENSP00000362963.4
	NONO	ENST00000373841.5	TSL:1	c.1171G>T	p.Gly391Cys	missense splice_region	Exon 9 of 11	ENSP00000362947.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.40		Loss of helix (P = 0.0068)
MVP		0.94
MPC		2.4
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		3.6
Varity_R		0.79
gMVP		0.82
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 0

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

Other links and lift over

dbSNP: rs1114167441; hg19: chrX-70518358;