9-137800985-G-A

Variant names:

• chr9-137800985-G-A
• rs1057518849
• NM_024757.5:c.2712+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_024757.5(EHMT1):​c.2712+1G>A variant causes a splice donor, intron 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 (★★). ClinVar reports functional evidence for this variant: "SCV005422227: The variant was absent in 251112 control chromosomes. c.2712+1G>A has been reported in the literature de novo in at least 2 individuals affected with Kleefstra Syndrome 1 (example, Rump_2013, Torga_2018). The following publications have been ascertained in the context of this evaluation (PMID:23232695, 30370152). **At least one publication reports experimental evidence that this variant affects mRNA splicing in patient cells, resulting in multiple aberrant transcript species which either skip exon 18 (in frame) or include 4 base pairs of intronic sequence (frameshift expected)** (example, Rump_2013).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: EHMT1 NM_024757.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.79
• Publications: 5 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 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.026943803 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005422227: The variant was absent in 251112 control chromosomes. c.2712+1G>A has been reported in the literature de novo in at least 2 individuals affected with Kleefstra Syndrome 1 (example, Rump_2013, Torga_2018). The following publications have been ascertained in the context of this evaluation (PMID: 23232695, 30370152). **At least one publication reports experimental evidence that this variant affects mRNA splicing in patient cells, resulting in multiple aberrant transcript species which either skip exon 18 (in frame) or include 4 base pairs of intronic sequence (frameshift expected)** (example, Rump_2013).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-137800985-G-A is Pathogenic according to our data. Variant chr9-137800985-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 374034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2712+1G>A		splice_donor intron	N/A	NP_079033.4
	EHMT1	NM_001354263.2		c.2691+1G>A		splice_donor intron	N/A	NP_001341192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.2712+1G>A		splice_donor intron	N/A	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000896765.1		c.2784+1G>A		splice_donor intron	N/A	ENSP00000566824.1
	EHMT1	ENST00000896763.1		c.2688+1G>A		splice_donor intron	N/A	ENSP00000566822.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Kleefstra syndrome 1 (6)
4	-	-	not provided (4)
1	-	-	Polymicrogyria;C0311394:Difficulty walking;C0424503:Abnormal facial shape;C0557874:Global developmental delay (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.8
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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