rs1554777032

Variant names:

• chr9-128694007-G-GA
• rs1554777032
• NM_003011.4:c.777dupA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_003011.4(SET):​c.777dupA​(p.Asp260ArgfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: SET NM_003011.4 frameshift
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 6.38
• Publications: 0 publications found

Genes affected

SET (HGNC:10760): (SET nuclear proto-oncogene) The protein encoded by this gene inhibits acetylation of nucleosomes, especially histone H4, by histone acetylases (HAT). This inhibition is most likely accomplished by masking histone lysines from being acetylated, and the consequence is to silence HAT-dependent transcription. The encoded protein is part of a complex localized to the endoplasmic reticulum but is found in the nucleus and inhibits apoptosis following attack by cytotoxic T lymphocytes. This protein can also enhance DNA replication of the adenovirus genome. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

SET Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 58

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305868 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0671 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003011.4. 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
	SET	NM_003011.4	MANE Select	c.777dupA	p.Asp260ArgfsTer2	frameshift	Exon 7 of 8	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.816dupA	p.Asp273ArgfsTer2	frameshift	Exon 7 of 8	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.816dupA	p.Asp273ArgfsTer2	frameshift	Exon 8 of 9	NP_001361255.1	Q5VXV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SET	ENST00000322030.13	TSL:1 MANE Select	c.777dupA	p.Asp260ArgfsTer2	frameshift	Exon 7 of 8	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.816dupA	p.Asp273ArgfsTer2	frameshift	Exon 7 of 8	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.777dupA	p.Asp260ArgfsTer2	frameshift	Exon 7 of 7	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Dysgerminoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -6

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

Other links and lift over

dbSNP: rs1554777032; hg19: chr9-131456286; COSMIC: COSV59002160;