9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT

Variant names:

• chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT
• rs745491546
• NM_003011.4:c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT

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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000321 in 1,060,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000032 (0 hom.)
• 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, Cryptic splice site detected, with MaxEntScore 3.4, offset of 47, new splice context is: aatGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it 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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		splice_donor intron	N/A	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		intron	N/A	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		splice_donor intron	N/A	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGATGAAGTACAAAAT		splice_donor intron	N/A	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.000121 AC: 12 AN: 99180 AF XY: 0.000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000760

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000860

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000423

GnomAD4 exome AF: 0.0000321 AC: 34 AN: 1060112 Hom.: 0 Cov.: 15 AF XY: 0.0000407 AC XY: 21 AN XY: 516000

⚠️ 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: 41212

European-Finnish (FIN) AF: 0.0000649 AC: 2 AN: 30830

Middle Eastern (MID) AF: 0.000361 AC: 1 AN: 2768

European-Non Finnish (NFE) AF: 0.0000324 AC: 28 AN: 865084

Other (OTH) AF: 0.0000252 AC: 1 AN: 39746

⚠️ 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
Mutation Taster		=8/92	disease causing

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;