9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_003011.4(SET):c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT(p.Glu37LysfsTer18) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,060,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000019 ( 0 hom. )
Consequence
SET
NM_003011.4 frameshift, splice_region
NM_003011.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SET | NM_003011.4 | c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT | p.Glu37LysfsTer18 | frameshift_variant, splice_region_variant | ENST00000322030.13 | ||
SET | NM_001122821.2 | c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT | intron_variant | ||||
SET | NM_001248000.2 | c.47-1515_47-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT | intron_variant | ||||
SET | NM_001374326.1 | c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SET | ENST00000322030.13 | c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT | p.Glu37LysfsTer18 | frameshift_variant, splice_region_variant | 1 | NM_003011.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD3 exomes AF: 0.0000605 AC: 6AN: 99180Hom.: 0 AF XY: 0.0000516 AC XY: 3AN XY: 58128
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GnomAD4 exome AF: 0.00000189 AC: 2AN: 1060132Hom.: 0 Cov.: 15 AF XY: 0.00000388 AC XY: 2AN XY: 516010
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GnomAD4 genome ? Cov.: 29
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29
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, autosomal dominant 58 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 26, 2020 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PVS1. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at