9-128683905-A-G

Position:

• chr9-128683905-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001122821.2(SET):​c.10A>G​(p.Lys4Glu) variant causes a missense change involving the alteration of a non-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: 31)
• Consequence: SET NM_001122821.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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]

DYNC2I2 (HGNC:28296): (dynein 2 intermediate chain 2) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Defects in this gene are a cause of short-rib thoracic dysplasia 11 with or without polydactyly. [provided by RefSeq, Mar 2014]

HMGA1P4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31871715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SET	NM_001122821.2	c.10A>G	p.Lys4Glu	missense_variant	1/8		NP_001116293.1
SET	NM_001374326.1	c.10A>G	p.Lys4Glu	missense_variant	2/9		NP_001361255.1
DYNC2I2	XM_047424057.1	c.-133+461T>C		intron_variant			XP_047280013.1
DYNC2I2	XM_011519179.3	c.-133+461T>C		intron_variant			XP_011517481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SET	ENST00000372692.8	c.10A>G	p.Lys4Glu	missense_variant	1/8	1		ENSP00000361777.4
SET	ENST00000686840.1	c.10A>G	p.Lys4Glu	missense_variant	2/9			ENSP00000509032.1
SET	ENST00000686568.1	c.10A>G	p.Lys4Glu	missense_variant	1/7			ENSP00000508597.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

GeneDx

Oct 04, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	0.0056	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	.;M
PROVEAN	Uncertain	-3.5	D;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.019	D;T
Polyphen		0.96	.;P
Vest4		0.45
MutPred		0.36		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);
MVP		0.58
MPC		2.1
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.30
gMVP		0.40

Splicing

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: chr9-131446184;