rs45450992

Variant names:

• chr9-137754290-C-T
• rs45450992
• NM_024757.5:c.1368C>T
• EHMT1 p.Leu456Leu

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024757.5(EHMT1):​c.1368C>T​(p.Leu456Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,613,744 control chromosomes in the GnomAD database, including 6,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (458 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5698 hom.)
• Consequence: EHMT1 NM_024757.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0004163
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.568
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-137754290-C-T is Benign according to our data. Variant chr9-137754290-C-T is described in ClinVar as Benign. ClinVar VariationId is 65725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.568 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0848 is higher than 0.05.

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.1368C>T	p.Leu456Leu	splice_region synonymous	Exon 8 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.1347C>T	p.Leu449Leu	splice_region synonymous	Exon 8 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.1275C>T	p.Leu425Leu	splice_region synonymous	Exon 7 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.1368C>T	p.Leu456Leu	splice_region synonymous	Exon 8 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.1368C>T	p.Leu456Leu	splice_region synonymous	Exon 8 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.1440C>T	p.Leu480Leu	splice_region synonymous	Exon 9 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10935 AN: 152008 Hom.: 460 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0403

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.0832

GnomAD2 exomes AF: 0.0703 AC: 17662 AN: 251172 AF XY: 0.0744

Gnomad AFR exome AF: 0.0596

Gnomad AMR exome AF: 0.0455

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0888

Gnomad OTH exome AF: 0.0791

GnomAD4 exome AF: 0.0839 AC: 122696 AN: 1461618 Hom.: 5698 Cov.: 32 AF XY: 0.0848 AC XY: 61673 AN XY: 727110

African (AFR) AF: 0.0622 AC: 2082 AN: 33468

American (AMR) AF: 0.0476 AC: 2128 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3230 AN: 26132

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0838 AC: 7224 AN: 86250

European-Finnish (FIN) AF: 0.0357 AC: 1905 AN: 53400

Middle Eastern (MID) AF: 0.163 AC: 939 AN: 5754

European-Non Finnish (NFE) AF: 0.0901 AC: 100159 AN: 1111832

Other (OTH) AF: 0.0832 AC: 5021 AN: 60370

GnomAD4 genome AF: 0.0719 AC: 10937 AN: 152126 Hom.: 458 Cov.: 32 AF XY: 0.0696 AC XY: 5177 AN XY: 74374

African (AFR) AF: 0.0627 AC: 2600 AN: 41494

American (AMR) AF: 0.0612 AC: 936 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5170

South Asian (SAS) AF: 0.0721 AC: 347 AN: 4812

European-Finnish (FIN) AF: 0.0403 AC: 427 AN: 10586

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0866 AC: 5891 AN: 67990

Other (OTH) AF: 0.0818 AC: 173 AN: 2114

Alfa AF: 0.0833 Hom.: 1327

Bravo AF: 0.0731

Asia WGS AF: 0.0330 AC: 118 AN: 3478

EpiCase AF: 0.0954

EpiControl AF: 0.0994

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Kleefstra syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.49
PhyloP100		0.57
PromoterAI		0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45450992;

hg19: chr9-140648742;