rs45450992

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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:7

Conservation

PhyloP100: 0.568

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.1368C>T	p.Leu456Leu	splice_region_variant, synonymous_variant	Exon 8 of 27	ENST00000460843.6	NP_079033.4	Q9H9B1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6 link	c.1368C>T	p.Leu456Leu	splice_region_variant, synonymous_variant	Exon 8 of 27	5	NM_024757.5	ENSP00000417980.1		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.0719

AC:

10935

AN:

152008

Hom.:

460

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0848

AC XY:

61673

AN XY:

727110

show subpopulations

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.:

AF XY:

0.0696

AC XY:

5177

AN XY:

74374

show subpopulations

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 18, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

not provided

Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kleefstra syndrome 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over