9-128689590-C-T

Position:

• chr9-128689590-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 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. 11/15 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

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_benign. Variant got -3 ACMG points.

• PM1: In a chain Protein SET (size 288) in uniprot entity SET_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_003011.4
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SET. . Gene score misZ 2.6574 (greater than the threshold 3.09). Trascript score misZ 3.2041 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant non-syndromic intellectual disability, intellectual disability, autosomal dominant 58.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2099455).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SET	NM_003011.4	c.8C>T	p.Ala3Val	missense_variant	1/8	ENST00000322030.13
SET	NM_001122821.2	c.113-1580C>T		intron_variant
SET	NM_001248000.2	c.47-1580C>T		intron_variant
SET	NM_001374326.1	c.113-1580C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SET	ENST00000322030.13	c.8C>T	p.Ala3Val	missense_variant	1/8	1	NM_003011.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

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

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: 0.0000672

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000204

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2022

SET: PP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	0.98	D;D;D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1241295194; hg19: chr9-131451869;