9-128689655-G-GAAAAAGAACA

Variant names:

• chr9-128689655-G-GAAAAAGAACA
• rs745491546
• NM_003011.4:c.73_73+1insAAAAAGAACA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_003011.4(SET):​c.73_73+1insAAAAAGAACA 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: 0.00028 (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 Likely_pathogenic. Variant got 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 10, new splice context is: acaGTgaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SET	NM_003011.4	c.73_73+1insAAAAAGAACA		splice_donor_variant, intron_variant	Intron 1 of 7	ENST00000322030.13	NP_003002.2
SET	NM_001122821.2	c.113-1515_113-1514insAAAAAGAACA		intron_variant	Intron 1 of 7		NP_001116293.1
SET	NM_001374326.1	c.113-1515_113-1514insAAAAAGAACA		intron_variant	Intron 2 of 8		NP_001361255.1
SET	NM_001248000.2	c.47-1515_47-1514insAAAAAGAACA		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+1insAAAAAGAACA		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: 0.000276 AC: 292 AN: 1059026 Hom.: 0 Cov.: 15 AF XY: 0.000252 AC XY: 130 AN XY: 515480

Gnomad4 AFR exome AF: 0.0000457

Gnomad4 AMR exome AF: 0.000147

Gnomad4 ASJ exome AF: 0.0000618

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000170

Gnomad4 FIN exome AF: 0.0000973

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000176

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;