rs1057518849

Positions:

• chr9-137800985-G-A
• chr9-137800985-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_024757.5(EHMT1):​c.2712+1G>A variant causes a splice donor 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EHMT1 NM_024757.5 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.79

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.026687196 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-137800985-G-A is Pathogenic according to our data. Variant chr9-137800985-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 374034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.2712+1G>A		splice_donor_variant		ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.2712+1G>A		splice_donor_variant		5	NM_024757.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change affects a donor splice site in intron 18 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Kleefstra syndrome (PMID: 23232695, 30370152, 31623504). ClinVar contains an entry for this variant (Variation ID: 374034). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Mar 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. The substitution at this canonical splice site has been shown to result in a frameshift leading to a predicted loss of protein function through NMD (PMID 23232695) (intron 18 of 26). (P) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. The substitution at this canonical splice site has also been shown to result in skipping of exon 18 (PMID 23232695). (P) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early onset DOMINANT condition that is INTOLERANT to loss-of-function variants. (P) 0505 - Abnormal splicing is predicted by in silico tools and nucleotide is highly conserved. (P) 0604 - Variant is not located in an established domain, motif or hotspot. (N) 0704 - Comparable variant in relevant codon/region has low previous evidence for pathogenicity. A different variant in the same splice site, c.2712+1G>C, has also been previously reported in a clinical case (ClinVar). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple patients with Kleefstra syndrome, and was shown to be de novo on one occasion (ClinVar; PMID: 23232695, 30370152). (P) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2022	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31623504, 23232695, 30370152) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jan 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	EHMT1: PVS1, PS2, PM2 -

Polymicrogyria;C0311394:Difficulty walking;C0424503:Abnormal facial shape;C0557874:Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: 3
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518849; hg19: chr9-140695437; COSMIC: COSV71777240; COSMIC: COSV71777240;