X-71290744-C-T

Position:

• chrX-71290744-C-T

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.107C>T​(p.Pro36Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,071,986 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes 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: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: NONO NM_007363.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.72

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]

NONO (HGNC:):

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=0.088362515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NONO	NM_007363.5	c.107C>T	p.Pro36Leu	missense_variant	3/12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.107C>T	p.Pro36Leu	missense_variant	4/13		NP_001138880.1
NONO	NM_001145409.2	c.107C>T	p.Pro36Leu	missense_variant	2/11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1035C>T		intron_variant			NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.107C>T	p.Pro36Leu	missense_variant	3/12	1	NM_007363.5	ENSP00000276079.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000722 AC: 1 AN: 138417 Hom.: 0 AF XY: 0.0000249 AC XY: 1 AN XY: 40181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000851

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000373 AC: 4 AN: 1071986 Hom.: 0 Cov.: 30 AF XY: 0.00000288 AC XY: 1 AN XY: 346822

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000337

Gnomad4 SAS exome AF: 0.0000386

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.0000182 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability 34 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 17, 2024	This sequence variant is a single nucleotide substitution (C>T) at position 107 of the coding sequence of the NONO gene that results in a proline to leucine amino acid change at residue 36 of the non-POU domain containing octamer binding protein. This is a previously reported variant (ClinVar 1341844) that has not been observed in the literature in individuals affected by NONO-related disease, to our knowledge. This variant is present in 4 of 1185422 alleles (0.00034%), including 1 hemizygote, in the gnomAD v4.1.1 population dataset. Multiple bioinformatic tools predict that this amino acid change would be neutral, and the Pro36 residue at this position is moderately conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.18	T;T;T;T;T;T;.
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.70	.;.;T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.088	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N;N;N;N;N;D;N
REVEL	Benign	0.058
Sift	Benign	0.093	T;T;T;T;T;D;T
Sift4G	Benign	0.067	T;T;T;T;T;T;T
Polyphen		0.14	B;B;B;.;.;.;.
Vest4		0.35
MutPred		0.23		Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);Loss of glycosylation at P36 (P = 0.0025);
MVP		0.48
MPC		1.3
ClinPred		0.089	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.38

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: rs750695677; hg19: chrX-70510594;