9-128689590-C-T

Variant names:

• chr9-128689590-C-T
• rs1241295194
• NM_003011.4:c.8C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003011.4(SET):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,225,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: SET NM_003011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 58

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2099455).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003011.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SET	NM_003011.4	MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 8	NP_003002.2	Q01105-2
	SET	NM_001122821.2		c.113-1580C>T		intron	N/A	NP_001116293.1	Q5VXV3
	SET	NM_001374326.1		c.113-1580C>T		intron	N/A	NP_001361255.1	Q5VXV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SET	ENST00000322030.13	TSL:1 MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 8	ENSP00000318012.9	Q01105-2
	SET	ENST00000372692.8	TSL:1	c.113-1580C>T		intron	N/A	ENSP00000361777.4	Q01105-1
	SET	ENST00000372688.9	TSL:2	c.8C>T	p.Ala3Val	missense	Exon 1 of 7	ENSP00000361773.5	A0A0C4DFV9

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000175 AC: 2 AN: 114314 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000490 AC: 6 AN: 1225566 Hom.: 0 Cov.: 25 AF XY: 0.00000661 AC XY: 4 AN XY: 604940

African (AFR) AF: 0.00 AC: 0 AN: 25508

American (AMR) AF: 0.00 AC: 0 AN: 27394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19810

East Asian (EAS) AF: 0.00 AC: 0 AN: 26562

South Asian (SAS) AF: 0.0000672 AC: 4 AN: 59498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3376

European-Non Finnish (NFE) AF: 0.00000204 AC: 2 AN: 978034

Other (OTH) AF: 0.00 AC: 0 AN: 47480

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Benign	0.92
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.3
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Benign	0.098	T
Sift4G	Benign	0.087	T
Polyphen		0.086	B
Vest4		0.13
MVP		0.34
ClinPred		0.034	T
GERP RS		2.3
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1241295194; hg19: chr9-131451869;