rs1554852591

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_024757.5(EHMT1):​c.676G>A​(p.Glu226Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.1332989).
BS2
High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EHMT1NM_024757.5 linkc.676G>A p.Glu226Lys missense_variant Exon 4 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.676G>A p.Glu226Lys missense_variant Exon 4 of 27 5 NM_024757.5 ENSP00000417980.1 Q9H9B1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251482
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135922
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kleefstra syndrome 1 Uncertain:1
Jul 30, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 226 of the EHMT1 protein (p.Glu226Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EHMT1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.069
T
BayesDel_noAF
Benign
-0.34
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.095
T;.;T;T;.;.
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.089
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.13
T;T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.2
L;L;.;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-0.67
N;N;.;.;.;.
REVEL
Benign
0.065
Sift
Uncertain
0.018
D;D;.;.;.;.
Sift4G
Benign
0.15
T;T;.;.;T;.
Polyphen
0.18
B;P;.;.;.;.
Vest4
0.13
MutPred
0.22
Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);Gain of MoRF binding (P = 0.0045);.;.;.;
MVP
0.53
MPC
0.058
ClinPred
0.63
D
GERP RS
5.2
Varity_R
0.24
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554852591; hg19: chr9-140622834; API