X-71290756-C-G

Variant names:

• chrX-71290756-C-G
• NM_007363.5:c.119C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40S) has been classified 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21308362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NONO	NM_007363.5	c.119C>G	p.Pro40Arg	missense_variant	Exon 3 of 12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.119C>G	p.Pro40Arg	missense_variant	Exon 4 of 13		NP_001138880.1
NONO	NM_001145409.2	c.119C>G	p.Pro40Arg	missense_variant	Exon 2 of 11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1023C>G		intron_variant	Intron 1 of 9		NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.119C>G	p.Pro40Arg	missense_variant	Exon 3 of 12	1	NM_007363.5	ENSP00000276079.8

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

May 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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). -

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;.;.;.;.
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;