rs1554776342

Variant names:

• chr9-128691221-TAGAC-T
• rs1554776342
• ENST00000322030.13:c.115_118delACAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003011.4(SET):​c.128_131delACAG​(p.Arg44LeufsTer10) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SET NM_003011.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 9.20
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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
• PP5: Variant 9-128691221-TAGAC-T is Pathogenic according to our data. Variant chr9-128691221-TAGAC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.128_131delACAG	p.Arg44LeufsTer10	frameshift splice_region	Exon 2 of 8	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.167_170delACAG	p.Arg57LeufsTer10	frameshift splice_region	Exon 2 of 8	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.167_170delACAG	p.Arg57LeufsTer10	frameshift splice_region	Exon 3 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.115_118delACAG	p.Gln39LeufsTer10	frameshift	Exon 2 of 8	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.154_157delACAG	p.Gln52LeufsTer10	frameshift	Exon 2 of 8	ENSP00000361777.4	Q01105-1
	SET	ENST00000477806.5	TSL:1	n.306_309delACAG		non_coding_transcript_exon	Exon 2 of 7

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Intellectual disability, autosomal dominant 58 (7)
2	-	-	not provided (2)
1	-	-	Global developmental delay (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
-	-	-	SET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554776342; hg19: chr9-131453500;