rs137852726

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_024757.5(EHMT1):​c.3218G>A​(p.Cys1073Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EHMT1
NM_024757.5 missense

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.82
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain Pre-SET (size 63) in uniprot entity EHMT1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_024757.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 9-137814468-G-A is Pathogenic according to our data. Variant chr9-137814468-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3607.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-137814468-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EHMT1NM_024757.5 linkuse as main transcriptc.3218G>A p.Cys1073Tyr missense_variant 22/27 ENST00000460843.6 NP_079033.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EHMT1ENST00000460843.6 linkuse as main transcriptc.3218G>A p.Cys1073Tyr missense_variant 22/275 NM_024757.5 ENSP00000417980 Q9H9B1-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:2Other:1
Pathogenic, criteria provided, single submittercurationLaboratory of Genetics, Children's Clinical University Hospital Latvia-- -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.84
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.3
H;.
MutationTaster
Benign
1.0
A
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-10
D;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.99
MutPred
0.95
Loss of stability (P = 0.0736);.;
MVP
0.97
MPC
2.3
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.99
gMVP
0.99

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

LitVar

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

Other links and lift over

dbSNP: rs137852726; hg19: chr9-140708920; API