9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATT

Variant names:

• chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATT
• rs745491546
• NM_003011.4:c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATT

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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,060,126 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: 0.0000075 (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, 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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATT		splice_donor intron	N/A	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATT		intron	N/A	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATT		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+1insAAAAAGAACAGCAAGAAGCGATTGAACACATT		splice_donor intron	N/A	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATT		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATT		splice_donor intron	N/A	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000605 AC: 6 AN: 99180 AF XY: 0.0000516

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: 0.0000737

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 8 AN: 1060126 Hom.: 0 Cov.: 15 AF XY: 0.00000775 AC XY: 4 AN XY: 516004

⚠️ 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: 20364

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 41214

European-Finnish (FIN) AF: 0.0000973 AC: 3 AN: 30824

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

European-Non Finnish (NFE) AF: 0.00000462 AC: 4 AN: 865104

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000159318), 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;