rs33999936

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3016G>A(p.Val1006Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,610,686 control chromosomes in the GnomAD database, including 3 homozygotes. 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. V1006L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 2 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.112

Publications

4 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: Ambry Genetics, G2P, 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=0.010900438).

BP6

Variant 9-137813154-G-A is Benign according to our data. Variant chr9-137813154-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00168 (256/152288) while in subpopulation AFR AF = 0.00563 (234/41572). AF 95% confidence interval is 0.00504. There are 1 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 256 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.3016G>A	p.Val1006Met	missense	Exon 20 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.2995G>A	p.Val999Met	missense	Exon 20 of 27	NP_001341192.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3016G>A	p.Val1006Met	missense	Exon 20 of 27	ENSP00000417980.1	Q9H9B1-1
EHMT1	ENST00000896765.1		c.3088G>A	p.Val1030Met	missense	Exon 21 of 28	ENSP00000566824.1
EHMT1	ENST00000896763.1		c.2992G>A	p.Val998Met	missense	Exon 20 of 27	ENSP00000566822.1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00565

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000391

AC:

AN:

247956

AF XY:

0.000335

show subpopulations

Gnomad AFR exome

AF:

0.00515

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0000531

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000171

AC:

250

AN:

1458398

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

725758

show subpopulations

African (AFR)

AF:

0.00601

AC:

201

AN:

33468

American (AMR)

AF:

0.000268

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000600

AC:

AN:

50036

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111958

Other (OTH)

AF:

0.000182

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152288

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00563

AC:

234

AN:

41572

American (AMR)

AF:

0.000588

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000545

Hom.:

Bravo

AF:

0.00164

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000478

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

EHMT1-related disorder (1)

Inborn genetic diseases (1)

Kleefstra syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

8.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.064

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.77

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.6

PhyloP100

-0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.59

REVEL

Benign

0.12

Sift

Benign

0.067

Sift4G

Benign

0.26

Polyphen

0.0050

Vest4

0.13

MVP

0.44

MPC

0.72

ClinPred

0.0083

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.49

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over