NM_024757.5:c.2426C>G

Variant names:

• chr9-137790891-C-G
• NM_024757.5:c.2426C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_024757.5(EHMT1):​c.2426C>G​(p.Pro809Arg) 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 pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P809L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137790891-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 9-137790891-C-G is Pathogenic according to our data. Variant chr9-137790891-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1791094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.2426C>G	p.Pro809Arg	missense_variant	Exon 16 of 27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.2426C>G	p.Pro809Arg	missense_variant	Exon 16 of 27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 29, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P809R variant (also known as c.2426C>G), located in coding exon 16 of the EHMT1 gene, results from a C to G substitution at nucleotide position 2426. The proline at codon 809 is replaced by arginine, an amino acid with dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of EHMT1-related neurological disorder (Ambry internal data). Based on internal structural analysis, this alteration is predicted to destabilize the interface between ankyrin repeats 2 and 3, of the ankyrin domain (Collins RE et al. Nat. Struct. Mol. Biol., 2008 Mar;15:245-50). In addition, a different alteration located at the same position, p.P809L, has been detected (once as a de novo occurrence) in two individuals with Kleefstra syndrome (KS) phenotypes. Authors also used structural and functional studies to show that the p.P809L variant likely has a deleterious impact on function; however, the direct link to pathology of unfolding in this domain was not completely characterized (Blackburn PR et al. J. Biol. Chem., 2017 Mar;292:3866-3876).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.0	H;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.0	D;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.79		Loss of glycosylation at P809 (P = 0.1028);.;.;
MVP		0.85
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140685343;