chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT

Position:

• chr9-128689655-G-GAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT

Variant summary

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

The NM_003011.4(SET):​c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 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 splice_donor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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/exons	MANE	Protein	UniProt
SET	NM_003011.4	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT		splice_donor_variant, intron_variant		ENST00000322030.13	NP_003002.2
SET	NM_001122821.2	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT		intron_variant			NP_001116293.1
SET	NM_001374326.1	c.113-1515_113-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT		intron_variant			NP_001361255.1
SET	NM_001248000.2	c.47-1515_47-1514insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT		intron_variant			NP_001234929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000322030.13	c.73_73+1insAAAAAGAACAGCAAGAAGCGATTGAACACATTGAT		splice_donor_variant, intron_variant		1	NM_003011.4	ENSP00000318012.9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.0000605 AC: 6 AN: 99180 Hom.: 0 AF XY: 0.0000516 AC XY: 3 AN XY: 58128

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 SAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.0000860

Gnomad NFE exome AF: 0.0000737

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000189 AC: 2 AN: 1060132 Hom.: 0 Cov.: 15 AF XY: 0.00000388 AC XY: 2 AN XY: 516010

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: 0.00

Gnomad4 FIN exome AF: 0.0000649

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

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;