NM_024757.5:c.2426C>G

Variant names:

• chr9-137790891-C-G
• rs587780332
• NM_024757.5:c.2426C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002737333: 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" and additional evidence is available in ClinVar. 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
• Publications: 0 publications found

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]

EHMT1 Gene-Disease associations (from GenCC):

• Kleefstra syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Kleefstra syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002737333: 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). 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).
• 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 ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 128978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 VariationId is 1791094.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.2426C>G	p.Pro809Arg	missense	Exon 16 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.2405C>G	p.Pro802Arg	missense	Exon 16 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.2333C>G	p.Pro778Arg	missense	Exon 15 of 16	NP_001341188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.2426C>G	p.Pro809Arg	missense	Exon 16 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000896765.1		c.2498C>G	p.Pro833Arg	missense	Exon 17 of 28	ENSP00000566824.1
	EHMT1	ENST00000896763.1		c.2402C>G	p.Pro801Arg	missense	Exon 16 of 27	ENSP00000566822.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.8
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
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs587780332; hg19: chr9-140685343;