chrX-71291820-G-A

Position:

• chrX-71291820-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007363.5(NONO):​c.196G>A​(p.Gly66Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,216 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: NONO NM_007363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.196G>A	p.Gly66Arg	missense_variant	4/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.196G>A	p.Gly66Arg	missense_variant	5/13		NP_001138880.1
NONO	NM_001145409.2	c.196G>A	p.Gly66Arg	missense_variant	3/11		NP_001138881.1
NONO	NM_001145410.2	c.-72G>A		5_prime_UTR_variant	2/10		NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.196G>A	p.Gly66Arg	missense_variant	4/12	1	NM_007363.5	ENSP00000276079	P1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112216 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34380

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112216 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000955

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Dec 07, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 66 of the NONO protein (p.Gly66Arg). This variant is present in population databases (no rsID available, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with NONO-related conditions. ClinVar contains an entry for this variant (Variation ID: 1917731). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NONO protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;D;D;D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D;D;D;D;D;T
Sift4G	Benign	0.26	T;T;T;D;T;T
Polyphen		0.74	P;P;P;.;.;.
Vest4		0.65
MutPred		0.34		Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);
MVP		0.91
MPC		1.6
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1204992623; hg19: chrX-70511670; COSMIC: COSV104579835; COSMIC: COSV104579835;