dbSNP rs78104547: EHMT1:p.Ala50Thr (chr9-137716688-G-A) – ACMG Classification: Benign (-20 pts)

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.148G>A(p.Ala50Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,606,096 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.475

Publications

8 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=0.0017711818).

BP6

Variant 9-137716688-G-A is Benign according to our data. Variant chr9-137716688-G-A is described in ClinVar as Benign. ClinVar VariationId is 128976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00209 (318/152176) while in subpopulation EAS AF = 0.0515 (267/5188). AF 95% confidence interval is 0.0464. There are 8 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 318 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EHMT1	NM_024757.5	MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 3 of 27	NP_079033.4
EHMT1	NM_001354263.2		c.148G>A	p.Ala50Thr	missense	Exon 3 of 27	NP_001341192.1
EHMT1	NM_001354259.2		c.55G>A	p.Ala19Thr	missense	Exon 2 of 16	NP_001341188.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.148G>A	p.Ala50Thr	missense	Exon 3 of 27	ENSP00000417980.1
EHMT1	ENST00000462484.5	TSL:1	c.148G>A	p.Ala50Thr	missense	Exon 3 of 16	ENSP00000417328.1
EHMT1	ENST00000637161.1	TSL:5	c.55G>A	p.Ala19Thr	missense	Exon 3 of 27	ENSP00000490328.1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0515

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00436

AC:

1084

AN:

248620

AF XY:

0.00375

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0550

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00142

AC:

2059

AN:

1453920

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

992

AN XY:

721902

show subpopulations

African (AFR)

AF:

0.0000901

AC:

AN:

33304

American (AMR)

AF:

0.000202

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.0399

AC:

1577

AN:

39524

South Asian (SAS)

AF:

0.00151

AC:

130

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52324

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000913

AC:

101

AN:

1106486

Other (OTH)

AF:

0.00395

AC:

237

AN:

60028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

123

246

368

491

614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00209

AC:

318

AN:

152176

Hom.:

Cov.:

AF XY:

0.00215

AC XY:

160

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41472

American (AMR)

AF:

0.000850

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0515

AC:

267

AN:

5188

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67974

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00155

Hom.:

Bravo

AF:

0.00249

ExAC

AF:

0.00420

AC:

510

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Feb 14, 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.

Inborn genetic diseases

Benign:1

Apr 20, 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.

Kleefstra syndrome 1

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.8

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

0.47

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.83

REVEL

Benign

0.050

Sift

Benign

0.076

Sift4G

Benign

0.25

Polyphen

0.031

Vest4

0.14

MVP

0.38

MPC

0.045

ClinPred

0.0029

GERP RS

1.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.7

Varity_R

0.035

gMVP

0.12

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over