9-128689655-G-GAAAAAGAACAGCAAGAAGCGATT

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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. 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SET	NM_003011.4	c.73_73+1insAAAAAGAACAGCAAGAAGCGATT		splice_donor_variant, intron_variant	Intron 1 of 7	ENST00000322030.13	NP_003002.2
SET	NM_001122821.2	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATT		intron_variant	Intron 1 of 7		NP_001116293.1
SET	NM_001374326.1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATT		intron_variant	Intron 2 of 8		NP_001361255.1
SET	NM_001248000.2	c.47-1515_47-1514insAAAAAGAACAGCAAGAAGCGATT		intron_variant	Intron 1 of 7		NP_001234929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000322030.13	c.73_73+1insAAAAAGAACAGCAAGAAGCGATT		splice_donor_variant, intron_variant	Intron 1 of 7	1	NM_003011.4	ENSP00000318012.9

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000485

Gnomad4 FIN exome AF: 0.0000973

Gnomad4 NFE exome AF: 0.0000890

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs745491546; hg19: chr9-131451934;