rs144603232

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024757.5(EHMT1):c.316C>G(p.Gln106Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,613,286 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 10 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.31

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Kleefstra syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Kleefstra syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

EHMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004447341).

BP6

Variant 9-137716856-C-G is Benign according to our data. Variant chr9-137716856-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 128981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00464 (707/152264) while in subpopulation AFR AF = 0.016 (663/41522). AF 95% confidence interval is 0.015. There are 10 homozygotes in GnomAd4. There are 339 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 707 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.316C>G	p.Gln106Glu	missense_variant	Exon 3 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.316C>G	p.Gln106Glu	missense_variant	Exon 3 of 27	5	NM_024757.5	ENSP00000417980.1		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00114

AC:

285

AN:

250960

AF XY:

0.000921

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000476

AC:

696

AN:

1461022

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

294

AN XY:

726768

show subpopulations

African (AFR)

AF:

0.0163

AC:

547

AN:

33478

American (AMR)

AF:

0.000828

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000379

AC:

AN:

52720

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000423

AC:

AN:

1111892

Other (OTH)

AF:

0.000994

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00464

AC:

707

AN:

152264

Hom.:

Cov.:

AF XY:

0.00455

AC XY:

339

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0160

AC:

663

AN:

41522

American (AMR)

AF:

0.00242

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

128

160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.00521

ESP6500AA

AF:

0.0127

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00130

AC:

158

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

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. -

Kleefstra syndrome 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 13, 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. -

EHMT1-related disorder

Benign:1

Apr 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.089

T;.;T;T;T;T;T;.;.;T

Eigen

Benign

0.053

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0044

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.2

M;M;.;.;.;.;.;.;.;.

PhyloP100

5.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.53

N;N;.;.;.;.;.;.;.;.

REVEL

Benign

0.081

Sift

Benign

0.14

T;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.53

T;T;T;D;.;.;T;T;.;T

Polyphen

0.49

P;P;.;.;.;.;.;.;.;.

Vest4

0.45

MVP

0.59

MPC

0.077

ClinPred

0.020

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.12

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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rs144603232

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over