rs45450992

chr9-137754290-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024757.5(EHMT1):c.1368C>T(p.Leu456=) 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:6
• Conservation: PhyloP100: 0.568

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 Benign. Variant got -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 id is 65725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137754290-C-T is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.1368C>T	p.Leu456=	splice_region_variant, synonymous_variant	8/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.1368C>T	p.Leu456=	splice_region_variant, synonymous_variant	8/27	5	NM_024757.5

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

GnomAD3 exomes AF: 0.0703 AC: 17662 AN: 251172 Hom.: 782 AF XY: 0.0744 AC XY: 10108 AN XY: 135778

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 SAS exome AF: 0.0822

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

Gnomad4 AFR exome AF: 0.0622

Gnomad4 AMR exome AF: 0.0476

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0838

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0901

Gnomad4 OTH exome AF: 0.0832

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

Gnomad4 AFR AF: 0.0627

Gnomad4 AMR AF: 0.0612

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0721

Gnomad4 FIN AF: 0.0403

Gnomad4 NFE AF: 0.0866

Gnomad4 OTH AF: 0.0818

Alfa AF: 0.0849 Hom.: 1055

Bravo AF: 0.0731

Asia WGS AF: 0.0330 AC: 118 AN: 3478

EpiCase AF: 0.0954

EpiControl AF: 0.0994

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.8
Dann	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs45450992; hg19: chr9-140648742;