NM_003011.4:c.73_73+1insAAAAAGAACAGCAAGAAGCGATT

Variant names:

• chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATT
• rs745491546
• NM_003011.4:c.73_73+1insAAAAAGAACAGCAAGAAGCGATT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_003011.4(SET):​c.73_73+1insAAAAAGAACAGCAAGAAGCGATT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000083 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SET NM_003011.4 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

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.73_73+1insAAAAAGAACAGCAAGAAGCGATT		splice_donor intron	N/A	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATT		intron	N/A	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATT		intron	N/A	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.73_73+1insAAAAAGAACAGCAAGAAGCGATT		splice_donor intron	N/A	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATT		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.73_73+1insAAAAAGAACAGCAAGAAGCGATT		splice_donor intron	N/A	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000830 AC: 88 AN: 1059972 Hom.: 0 Cov.: 15 AF XY: 0.0000814 AC XY: 42 AN XY: 515934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21878

American (AMR) AF: 0.00 AC: 0 AN: 20366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16182

East Asian (EAS) AF: 0.00 AC: 0 AN: 22046

South Asian (SAS) AF: 0.0000485 AC: 2 AN: 41206

European-Finnish (FIN) AF: 0.0000973 AC: 3 AN: 30834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2768

European-Non Finnish (NFE) AF: 0.0000890 AC: 77 AN: 864952

Other (OTH) AF: 0.000151 AC: 6 AN: 39740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0

Splicing

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

Other links and lift over

dbSNP: rs745491546; hg19: chr9-131451934;