X-71290741-A-C

Position:

• chrX-71290741-A-C

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.104A>C​(p.Gln35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,075,324 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: NONO NM_007363.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

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=0.13404292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.104A>C	p.Gln35Pro	missense_variant	3/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.104A>C	p.Gln35Pro	missense_variant	4/13		NP_001138880.1
NONO	NM_001145409.2	c.104A>C	p.Gln35Pro	missense_variant	2/11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1038A>C		intron_variant			NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.104A>C	p.Gln35Pro	missense_variant	3/12	1	NM_007363.5	ENSP00000276079	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000372 AC: 4 AN: 1075324 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 349086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.0000222

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000179 AC: 2

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

GeneDx

Sep 01, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T;T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	.;.;T;T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L;.;.;.;.
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.27	N;N;N;N;N;D;N
REVEL	Benign	0.080
Sift	Benign	0.22	T;T;T;T;T;T;T
Sift4G	Benign	0.10	T;T;T;D;T;D;D
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.37
MutPred		0.34		Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);Gain of glycosylation at Q35 (P = 0.0014);
MVP		0.68
MPC		2.1
ClinPred		0.24	T
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.46

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: rs767664432; hg19: chrX-70510591;