chrX-71290779-G-T

Position:

• chrX-71290779-G-T

Variant summary

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

The ENST00000276079.13(NONO):​c.142G>T​(p.Ala48Ser) variant causes a missense 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NONO ENST00000276079.13 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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=0.16859221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.142G>T	p.Ala48Ser	missense_variant	3/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.142G>T	p.Ala48Ser	missense_variant	4/13		NP_001138880.1
NONO	NM_001145409.2	c.142G>T	p.Ala48Ser	missense_variant	2/11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1000G>T		intron_variant			NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.142G>T	p.Ala48Ser	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

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Jul 25, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	.;.;T;T;T;D;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.21	N;N;N;N;N;D;N
REVEL	Benign	0.075
Sift	Benign	0.17	T;T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;T;T
Polyphen		0.017	B;B;B;.;.;.;.
Vest4		0.30
MutPred		0.19		Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);Gain of glycosylation at A48 (P = 0.0514);
MVP		0.62
MPC		1.3
ClinPred		0.45	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1569238685; hg19: chrX-70510629;