rs141282876

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_024757.5(EHMT1):c.499G>A(p.Ala167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000573 in 1,606,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A167D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.873

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023327678).

BP6

Variant 9-137717039-G-A is Benign according to our data. Variant chr9-137717039-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 531857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 7 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.499G>A	p.Ala167Thr	missense	Exon 3 of 27	NP_079033.4
EHMT1	NM_001354263.2		c.499G>A	p.Ala167Thr	missense	Exon 3 of 27	NP_001341192.1
EHMT1	NM_001354259.2		c.406G>A	p.Ala136Thr	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.499G>A	p.Ala167Thr	missense	Exon 3 of 27	ENSP00000417980.1
EHMT1	ENST00000462484.5	TSL:1	c.499G>A	p.Ala167Thr	missense	Exon 3 of 16	ENSP00000417328.1
EHMT1	ENST00000637161.1	TSL:5	c.406G>A	p.Ala136Thr	missense	Exon 3 of 27	ENSP00000490328.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000607

AC:

AN:

247106

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000450

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000584

AC:

AN:

1454626

Hom.:

Cov.:

AF XY:

0.0000554

AC XY:

AN XY:

722624

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33228

American (AMR)

AF:

0.00

AC:

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.000221

AC:

AN:

86086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000578

AC:

AN:

1107758

Other (OTH)

AF:

0.00

AC:

AN:

60034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000388

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000907

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kleefstra syndrome 1

Benign:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

May 01, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

not provided

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EHMT1 p.Ala167Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141282876) and in ClinVar (classified as a VUS by Invitae and as likely benign by Ambry Genetics). The variant was identified in control databases in 15 of 247106 chromosomes at a frequency of 0.000061 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 10 of 30416 chromosomes (freq: 0.000329) and European (non-Finnish) in 5 of 111096 chromosomes (freq: 0.000045), but not in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The p.Ala167 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

EHMT1-related disorder

Benign:1

Jul 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.050

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.73

M_CAP

Benign

0.041

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-0.87

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.090

REVEL

Benign

0.045

Sift

Benign

0.32

Sift4G

Benign

0.43

Polyphen

0.0010

Vest4

0.070

MVP

0.41

MPC

0.045

ClinPred

0.026

GERP RS

0.024

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.021

gMVP

0.095

Mutation Taster

=97/3

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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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