rs756534222

Variant names:

• chrX-71290703-TCACCACCAGCAGCAG-T
• rs756534222
• NM_007363.5:c.81_95delGCACCACCAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007363.5(NONO):​c.81_95delGCACCACCAGCAGCA​(p.His28_Gln32del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000512 in 1,093,127 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000051 (0 hom. 14 hem.)
• Consequence: NONO NM_007363.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.85

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NONO	NM_007363.5	c.81_95delGCACCACCAGCAGCA	p.His28_Gln32del	disruptive_inframe_deletion	Exon 3 of 12	ENST00000276079.13	NP_031389.3
NONO	NM_001145408.2	c.81_95delGCACCACCAGCAGCA	p.His28_Gln32del	disruptive_inframe_deletion	Exon 4 of 13		NP_001138880.1
NONO	NM_001145409.2	c.81_95delGCACCACCAGCAGCA	p.His28_Gln32del	disruptive_inframe_deletion	Exon 2 of 11		NP_001138881.1
NONO	NM_001145410.2	c.-113-1061_-113-1047delGCACCACCAGCAGCA		intron_variant	Intron 1 of 9		NP_001138882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NONO	ENST00000276079.13	c.81_95delGCACCACCAGCAGCA	p.His28_Gln32del	disruptive_inframe_deletion	Exon 3 of 12	1	NM_007363.5	ENSP00000276079.8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000116 AC: 2 AN: 171854 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 58720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000512 AC: 56 AN: 1093127 Hom.: 0 AF XY: 0.0000390 AC XY: 14 AN XY: 358757

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000375

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.000131

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NONO: PM2, BP3 -

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.81_95del, results in the deletion of 5 amino acid(s) of the NONO protein (p.His28_Gln32del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs756534222, gnomAD 0.003%). 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: 1319296). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Syndromic X-linked intellectual disability 34 Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs756534222; hg19: chrX-70510553;