rs869025295

Variant names:

• chr17-16067927-GA-G
• rs869025295
• NM_006311.4:c.4707delT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006311.4(NCOR1):​c.4707delT​(p.Pro1570GlnfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCOR1 NM_006311.4 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.96
• Publications: 1 publications found

Genes affected

NCOR1 (HGNC:7672): (nuclear receptor corepressor 1) This gene encodes a protein that mediates ligand-independent transcription repression of thyroid-hormone and retinoic-acid receptors by promoting chromatin condensation and preventing access of the transcription machinery. It is part of a complex which also includes histone deacetylases and transcriptional regulators similar to the yeast protein Sin3p. This gene is located between the Charcot-Marie-Tooth and Smith-Magenis syndrome critical regions on chromosome 17. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 17 and 20.[provided by RefSeq, Jun 2010]

NCOR1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006311.4. 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
	NCOR1	NM_006311.4	MANE Select	c.4707delT	p.Pro1570GlnfsTer45	frameshift	Exon 32 of 46	NP_006302.2
	NCOR1	NM_001439111.1		c.4929delT	p.Pro1644GlnfsTer45	frameshift	Exon 33 of 47	NP_001426040.1
	NCOR1	NM_001439112.1		c.4785delT	p.Pro1596GlnfsTer45	frameshift	Exon 34 of 48	NP_001426041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR1	ENST00000268712.8	TSL:1 MANE Select	c.4707delT	p.Pro1570GlnfsTer45	frameshift	Exon 32 of 46	ENSP00000268712.2	O75376-1
	NCOR1	ENST00000436068.2	TSL:1	c.4929delT	p.Pro1644GlnfsTer45	frameshift	Exon 33 of 47	ENSP00000389839.2	H0Y459
	NCOR1	ENST00000395851.5	TSL:1	c.4755delT	p.Pro1586GlnfsTer45	frameshift	Exon 31 of 45	ENSP00000379192.1	O75376-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

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: rs869025295; hg19: chr17-15971241; COSMIC: COSV51969189;