9-128689655-G-GAAAAA

Variant names:

• chr9-128689655-G-GAAAAA
• rs745491546
• NM_003011.4:c.73_73+1insAAAAA

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+1insAAAAA variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. 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: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00013 (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, G2P, Labcorp Genetics (formerly Invitae)
• 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 4.2, offset of 5, new splice context is: aaaGTgaga. 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+1insAAAAA		splice_donor intron	N/A	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.113-1515_113-1514insAAAAA		intron	N/A	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.113-1515_113-1514insAAAAA		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+1insAAAAA		splice_donor intron	N/A	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1515_113-1514insAAAAA		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.73_73+1insAAAAA		splice_donor intron	N/A	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147374 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000524 AC: 52 AN: 99180 AF XY: 0.000551

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000258

Gnomad NFE exome AF: 0.000958

Gnomad OTH exome AF: 0.000845

GnomAD4 exome AF: 0.000131 AC: 139 AN: 1059708 Hom.: 0 Cov.: 15 AF XY: 0.000136 AC XY: 70 AN XY: 515824

⚠️ 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: 0.0000491 AC: 1 AN: 20358

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

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

South Asian (SAS) AF: 0.000340 AC: 14 AN: 41206

European-Finnish (FIN) AF: 0.000195 AC: 6 AN: 30814

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

European-Non Finnish (NFE) AF: 0.000128 AC: 111 AN: 864726

Other (OTH) AF: 0.000176 AC: 7 AN: 39730

⚠️ 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 Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 147374 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 71766

African (AFR) AF: 0.00 AC: 0 AN: 40656

American (AMR) AF: 0.00 AC: 0 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 4924

South Asian (SAS) AF: 0.00 AC: 0 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66494

Other (OTH) AF: 0.00 AC: 0 AN: 2034

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=3/97	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;