rs35943616

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.3000C>T(p.Pro1000Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,611,890 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 2380 hom., cov: 33)

Exomes 𝑓: 0.010 ( 2127 hom. )

Consequence

EHMT1
NM_024757.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.12

Publications

6 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=-0.77).

BP6

Variant 9-137813138-C-T is Benign according to our data. Variant chr9-137813138-C-T is described in ClinVar as Benign. ClinVar VariationId is 96151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.12 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5 link	c.3000C>T	p.Pro1000Pro	synonymous_variant	Exon 20 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.3000C>T	p.Pro1000Pro	synonymous_variant	Exon 20 of 27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes

AF:

0.0970

AC:

14756

AN:

152078

Hom.:

2368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0377

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.0789

GnomAD2 exomes

AF:

0.0258

AC:

6434

AN:

249276

AF XY:

0.0187

show subpopulations

Gnomad AFR exome

AF:

0.343

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000978

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0101

AC:

14785

AN:

1459694

Hom.:

2127

Cov.:

AF XY:

0.00859

AC XY:

6241

AN XY:

726298

show subpopulations

African (AFR)

AF:

0.347

AC:

11619

AN:

33478

American (AMR)

AF:

0.0193

AC:

864

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00157

AC:

AN:

26136

East Asian (EAS)

AF:

0.00433

AC:

172

AN:

39698

South Asian (SAS)

AF:

0.000522

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51284

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000579

AC:

644

AN:

1111982

Other (OTH)

AF:

0.0219

AC:

1325

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

676

1352

2028

2704

3380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.0973

AC:

14810

AN:

152196

Hom.:

2380

Cov.:

AF XY:

0.0929

AC XY:

6913

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.337

AC:

13963

AN:

41476

American (AMR)

AF:

0.0376

AC:

575

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00348

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68016

Other (OTH)

AF:

0.0781

AC:

165

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

518

1037

1555

2074

2592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0435

Hom.:

628

Bravo

AF:

0.112

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -

May 21, 2014

Eurofins Ntd Llc (ga)

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 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 16, 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

-0.77

CADD

Benign

0.16

(source)

DANN

Benign

0.49

PhyloP100

-4.1

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)

0.030

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