9-137743964-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024757.5(EHMT1):c.1044G>A(p.Ser348Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,684 control chromosomes in the GnomAD database, including 28,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S348S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2436 hom., cov: 32)

Exomes 𝑓: 0.18 ( 26387 hom. )

Consequence

EHMT1
NM_024757.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.63

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 9-137743964-G-A is Benign according to our data. Variant chr9-137743964-G-A is described in ClinVar as Benign. ClinVar VariationId is 65723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.63 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.1044G>A	p.Ser348Ser	synonymous_variant	Exon 6 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.1044G>A	p.Ser348Ser	synonymous_variant	Exon 6 of 27	5	NM_024757.5	ENSP00000417980.1		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23203

AN:

152148

Hom.:

2428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0335

Gnomad AMI

AF:

0.260

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.198

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.184

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.158

GnomAD2 exomes

AF:

0.203

AC:

50848

AN:

250544

AF XY:

0.198

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.434

Gnomad ASJ exome

AF:

0.203

Gnomad EAS exome

AF:

0.0963

Gnomad FIN exome

AF:

0.183

Gnomad NFE exome

AF:

0.174

Gnomad OTH exome

AF:

0.184

GnomAD4 exome

AF:

0.181

AC:

264306

AN:

1461418

Hom.:

26387

Cov.:

AF XY:

0.183

AC XY:

132775

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.0276

AC:

924

AN:

33480

American (AMR)

AF:

0.420

AC:

18764

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

5382

AN:

26128

East Asian (EAS)

AF:

0.113

AC:

4492

AN:

39696

South Asian (SAS)

AF:

0.228

AC:

19673

AN:

86248

European-Finnish (FIN)

AF:

0.181

AC:

9633

AN:

53216

Middle Eastern (MID)

AF:

0.122

AC:

702

AN:

5748

European-Non Finnish (NFE)

AF:

0.175

AC:

194491

AN:

1111856

Other (OTH)

AF:

0.170

AC:

10245

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13298

26596

39893

53191

66489

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6912

13824

20736

27648

34560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.153

AC:

23224

AN:

152266

Hom.:

2436

Cov.:

AF XY:

0.157

AC XY:

11683

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0334

AC:

1387

AN:

41572

American (AMR)

AF:

0.308

AC:

4702

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.198

AC:

688

AN:

3472

East Asian (EAS)

AF:

0.103

AC:

532

AN:

5178

South Asian (SAS)

AF:

0.229

AC:

1105

AN:

4824

European-Finnish (FIN)

AF:

0.184

AC:

1954

AN:

10606

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.180

AC:

12261

AN:

68008

Other (OTH)

AF:

0.158

AC:

333

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

975

1950

2925

3900

4875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

256

512

768

1024

1280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.166

Hom.:

2436

Bravo

AF:

0.157

Asia WGS

AF:

0.135

AC:

471

AN:

3478

EpiCase

AF:

0.179

EpiControl

AF:

0.168

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -

Sep 25, 2014

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

- -

Kleefstra syndrome 1

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 30, 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

- -

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

-0.75

CADD

Benign

0.28

(source)

DANN

Benign

0.76

PhyloP100

-4.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=99/1

polymorphism (auto)

(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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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