Genetic Variant SET:c.73_73+1insAAAAA (chr9-128689655-G-GAAAAA) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2

The NM_003011.4(SET):c.73_73+1insAAAAA variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. 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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.

BS2

High AC in GnomAdExome4 at 139 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SET	NM_003011.4 link	c.73_73+1insAAAAA	splice_donor_variant, intron_variant	Intron 1 of 7	ENST00000322030.13	NP_003002.2	Q01105-2A0A024R895
SET	NM_001122821.2 link	c.113-1515_113-1514insAAAAA	intron_variant	Intron 1 of 7		NP_001116293.1	Q01105-1Q5VXV3
SET	NM_001374326.1 link	c.113-1515_113-1514insAAAAA	intron_variant	Intron 2 of 8		NP_001361255.1
SET	NM_001248000.2 link	c.47-1515_47-1514insAAAAA	intron_variant	Intron 1 of 7		NP_001234929.1	Q01105-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000322030.13 link	c.73_73+1insAAAAA		splice_donor_variant, intron_variant	Intron 1 of 7	1	NM_003011.4	ENSP00000318012.9		Q01105-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147374

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.000524

AC:

AN:

99180

Hom.:

AF XY:

0.000551

AC XY:

AN XY:

58128

show subpopulations

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 SAS exome

AF:

0.000229

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.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

515824

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000491

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000340

Gnomad4 FIN exome

AF:

0.000195

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.000176

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

147374

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71766

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over