rs3812497

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.444T>C(p.Pro148Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,608,838 control chromosomes in the GnomAD database, including 62,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5098 hom., cov: 32)

Exomes 𝑓: 0.28 ( 57545 hom. )

Consequence

EHMT1
NM_024757.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.319

Publications

21 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=-0.54).

BP6

Variant 9-137716984-T-C is Benign according to our data. Variant chr9-137716984-T-C is described in ClinVar as Benign. ClinVar VariationId is 65738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.319 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.444T>C	p.Pro148Pro	synonymous_variant	Exon 3 of 27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6 link	c.444T>C	p.Pro148Pro	synonymous_variant	Exon 3 of 27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes

AF:

0.241

AC:

36622

AN:

152002

Hom.:

5091

Cov.:

show subpopulations

Gnomad AFR

AF:

0.117

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.346

Gnomad EAS

AF:

0.146

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.280

Gnomad OTH

AF:

0.252

GnomAD2 exomes

AF:

0.288

AC:

72036

AN:

249932

AF XY:

0.287

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.483

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.137

Gnomad FIN exome

AF:

0.252

Gnomad NFE exome

AF:

0.275

Gnomad OTH exome

AF:

0.277

GnomAD4 exome

AF:

0.275

AC:

400861

AN:

1456718

Hom.:

57545

Cov.:

AF XY:

0.277

AC XY:

200831

AN XY:

723724

show subpopulations

African (AFR)

AF:

0.109

AC:

3622

AN:

33354

American (AMR)

AF:

0.471

AC:

20976

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.349

AC:

9090

AN:

26060

East Asian (EAS)

AF:

0.146

AC:

5767

AN:

39620

South Asian (SAS)

AF:

0.317

AC:

27374

AN:

86232

European-Finnish (FIN)

AF:

0.252

AC:

13198

AN:

52290

Middle Eastern (MID)

AF:

0.301

AC:

1732

AN:

5748

European-Non Finnish (NFE)

AF:

0.273

AC:

303183

AN:

1108644

Other (OTH)

AF:

0.264

AC:

15919

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

19333

38665

57998

77330

96663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10174

20348

30522

40696

50870

<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:

0.241

AC:

36649

AN:

152120

Hom.:

5098

Cov.:

AF XY:

0.244

AC XY:

18112

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.117

AC:

4868

AN:

41522

American (AMR)

AF:

0.375

AC:

5721

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

1200

AN:

3468

East Asian (EAS)

AF:

0.146

AC:

755

AN:

5170

South Asian (SAS)

AF:

0.309

AC:

1492

AN:

4824

European-Finnish (FIN)

AF:

0.254

AC:

2691

AN:

10598

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.280

AC:

19003

AN:

67948

Other (OTH)

AF:

0.251

AC:

529

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1405

2810

4216

5621

7026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.272

Hom.:

9180

Bravo

AF:

0.244

Asia WGS

AF:

0.190

AC:

665

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 23, 2014

Eurofins Ntd Llc (ga)

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.

Kleefstra syndrome 1

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 05, 2018

GeneDx

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

-0.54

CADD

Benign

6.2

(source)

DANN

Benign

0.67

PhyloP100

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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