X-71290756-C-G

Position:

• chrX-71290756-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_007363.5(NONO):​c.119C>G​(p.Pro40Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NONO NM_007363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NONO. . Gene score misZ 3.5885 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked syndromic intellectual disability, autism, susceptibility to, 15, syndromic X-linked intellectual disability 34.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21308362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.119C>G	p.Pro40Arg	missense_variant	3/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.119C>G	p.Pro40Arg	missense_variant	4/13		NP_001138880.1
NONO	NM_001145409.2	c.119C>G	p.Pro40Arg	missense_variant	2/11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1023C>G		intron_variant			NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.119C>G	p.Pro40Arg	missense_variant	3/12	1	NM_007363.5	ENSP00000276079	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2022

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 40 of the NONO protein (p.Pro40Arg). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NONO-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	.;.;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.30	N;N;N;N;N;D;N
REVEL	Benign	0.039
Sift	Benign	0.071	T;T;T;T;T;D;T
Sift4G	Benign	0.25	T;T;T;D;T;D;T
Polyphen		0.24	B;B;B;.;.;.;.
Vest4		0.31
MutPred		0.23		Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);Loss of glycosylation at P40 (P = 0.0025);
MVP		0.54
MPC		1.4
ClinPred		0.68	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-70510606;