9-137790891-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_024757.5(EHMT1):​c.2426C>T​(p.Pro809Leu) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U: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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 9-137790891-C-T is Pathogenic according to our data. Variant chr9-137790891-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137790891-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.2426C>T	p.Pro809Leu	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>T	p.Pro809Leu	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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:4

-

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 13, 2024

Genetics Laboratory, The Affiliated Women's and Children's Hospital of Qingdao University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

c.2426C>T (exon16, NM_024757), resulting in the amino acid change p.P809L, a missense mutation. The mutation was initially determined to be a pathogenic mutation (Pathogenic) PS2+PS4+PM2+PP3 according to the ACMG guidelines:  PS2: After family validation analysis, there is no mutation at this locus in the subject's father and no mutation at this locus in the subject's mother, and this variant is a spontaneous mutation;  PS4: cases of this locus (Kleefstra syndrome) have been reported in the literature database, with the variant labeled DM (pathogenic mutation), ClinVar The pathogenicity analysis of this locus in the ClinVar database is Conflicting interpretations of pathogenicity,- ;  PM2: the frequency in the normal population database is -, a low-frequency variant;  PP3: Bioinformatics protein function comprehensive prediction software REVEL predicted the results as harmful, SIFT, PolyPhen_2, MutationTaster , GERP+ predicted the results as harmful, harmful, harmful, harmful, harmful, respectively; -

Feb 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects EHMT1 function (PMID: 28057753). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 128978). This missense change has been observed in individual(s) with clinical features of Kleefstra syndrome (PMID: 28057753, 29276005, 31785789, 33767182). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 809 of the EHMT1 protein (p.Pro809Leu). -

Sep 05, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EHMT1 c.2426C>T variant is classified as PATHOGENIC (PS2, PS3, PS4, PP3) The EHMT1 c.2426C>T variant is a single nucleotide change in exon 16/27 of the EHMT1 gene, which is predicted to change the amino acid proline at position 809 in the protein to leucine. This variant has been identified as a de novo variant in this patient, although was detected in a very small proportion of reads in the mother (2 of 72, ~3%) (PS2). It has also been reported as de novo in an individual with Kleefstra syndrome in the literature, along with another unrelated Kleefstra syndrome case (PMID: 28057753; PS4). This variant is absent from population databases (PM2). Functional studies have demonstrated the variant leads to protein misfolding and aberrant target recognition via disrupted histone mark binding (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has been reported in dbSNP (rs587780332) and has been reported as likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 128978), and damaging for Kleefstra syndrome in HGMD (CM172582). -

not provided Pathogenic:2 Uncertain:1

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.7	M;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.9	D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.79		Loss of disorder (P = 0.0443);.;.;
MVP		0.75
MPC		1.8
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.93

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: rs587780332; hg19: chr9-140685343; COSMIC: COSV58377558; COSMIC: COSV58377558;