rs1554846686

Positions:

• chr9-137717010-G-A

Variant summary

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

The NM_024757.5(EHMT1):​c.470G>A​(p.Gly157Glu) variant causes a missense change. 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: EHMT1 NM_024757.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

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=0.34417892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.470G>A	p.Gly157Glu	missense_variant	3/27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.470G>A	p.Gly157Glu	missense_variant	3/27	5	NM_024757.5	ENSP00000417980

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EHMT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 157 of the EHMT1 protein (p.Gly157Glu). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;T;T;T;.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.;.;.;.
MutationTaster	Benign	0.65	D;D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Uncertain	0.010	D;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.018	D;D;D;.;.;D;D;.;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.55
MutPred		0.17		Gain of ubiquitination at K153 (P = 0.0192);Gain of ubiquitination at K153 (P = 0.0192);.;Gain of ubiquitination at K153 (P = 0.0192);.;.;.;.;.;
MVP		0.55
MPC		0.28
ClinPred		0.85	D
GERP RS		5.1
Varity_R		0.094
gMVP		0.093

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: rs1554846686; hg19: chr9-140611462;