NM_024757.5:c.1177G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_024757.5(EHMT1):​c.1177G>A​(p.Gly393Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G393W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

1
8
10

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.69

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16769436).
BP6
Variant 9-137752337-G-A is Benign according to our data. Variant chr9-137752337-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2042740.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EHMT1NM_024757.5 linkc.1177G>A p.Gly393Arg missense_variant Exon 7 of 27 ENST00000460843.6 NP_079033.4 Q9H9B1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EHMT1ENST00000460843.6 linkc.1177G>A p.Gly393Arg missense_variant Exon 7 of 27 5 NM_024757.5 ENSP00000417980.1 Q9H9B1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000798
AC:
2
AN:
250532
AF XY:
0.00000738
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461796
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727196
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86234
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5740
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111988
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kleefstra syndrome 1 Benign:1
Jun 08, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.045
T
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.10
T;.;T;T;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.17
T;T;T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Uncertain
2.2
M;M;.;.;.;.
PhyloP100
3.7
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.4
N;N;.;.;.;.
REVEL
Benign
0.16
Sift
Uncertain
0.0020
D;D;.;.;.;.
Sift4G
Benign
0.20
T;T;.;.;.;.
Polyphen
1.0
D;D;.;.;.;.
Vest4
0.30
MutPred
0.23
Loss of ubiquitination at K390 (P = 0.0471);Loss of ubiquitination at K390 (P = 0.0471);Loss of ubiquitination at K390 (P = 0.0471);.;.;.;
MVP
0.55
MPC
0.064
ClinPred
0.69
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.12
gMVP
0.11
Mutation Taster
=71/29
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs772187480; hg19: chr9-140646789; API