9-128691868-C-G

Position:

• chr9-128691868-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_003011.4(SET):​c.142C>G​(p.Gln48Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SET NM_003011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.28

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a helix (size 50) in uniprot entity SET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003011.4
• PM2: Very rare variant in population databases, with high coverage
• 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=0.35036793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SET	NM_003011.4	c.142C>G	p.Gln48Glu	missense_variant	3/8	ENST00000322030.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SET	ENST00000322030.13	c.142C>G	p.Gln48Glu	missense_variant	3/8	1	NM_003011.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

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

Apr 01, 2023

SET: PM2, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.;.;.;.
Eigen	Benign	0.0020
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.020	B;.;B;.;.
Vest4		0.65
MutPred		0.47		Gain of phosphorylation at S63 (P = 0.111);.;.;.;.;
MVP		0.69
MPC		2.3
ClinPred		0.80	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-131454147;