NM_007363.5:c.107C>T

Variant names:

• chrX-71290744-C-T
• rs750695677
• NM_007363.5:c.107C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 14/21 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• syndromic X-linked intellectual disability 34

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.088362515).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007363.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	NM_007363.5	MANE Select	c.107C>T	p.Pro36Leu	missense	Exon 3 of 12	NP_031389.3
	NONO	NM_001145408.2		c.107C>T	p.Pro36Leu	missense	Exon 4 of 13	NP_001138880.1	A0A0S2Z4Z9
	NONO	NM_001145409.2		c.107C>T	p.Pro36Leu	missense	Exon 2 of 11	NP_001138881.1	Q15233-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NONO	ENST00000276079.13	TSL:1 MANE Select	c.107C>T	p.Pro36Leu	missense	Exon 3 of 12	ENSP00000276079.8	Q15233-1
	NONO	ENST00000373856.8	TSL:1	c.107C>T	p.Pro36Leu	missense	Exon 3 of 13	ENSP00000362963.4	A0A7P0MRW0
	NONO	ENST00000373841.5	TSL:1	c.107C>T	p.Pro36Leu	missense	Exon 2 of 11	ENSP00000362947.1	Q15233-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000722 AC: 1 AN: 138417 AF XY: 0.0000249

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 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

African (AFR) AF: 0.00 AC: 0 AN: 25983

American (AMR) AF: 0.00 AC: 0 AN: 33023

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18482

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29677

South Asian (SAS) AF: 0.0000386 AC: 2 AN: 51813

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38673

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4069

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 825388

Other (OTH) AF: 0.00 AC: 0 AN: 44878

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000182 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Syndromic X-linked intellectual disability 34 (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.058
Sift	Benign	0.093	T
Sift4G	Benign	0.067	T
Polyphen		0.14	B
Vest4		0.35
MutPred		0.23		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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs750695677; hg19: chrX-70510594; COSMIC: COSV108053765; COSMIC: COSV108053765;