rs397515548
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_004456.5(EZH2):c.2233G>A(p.Glu745Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E745D) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
EZH2
NM_004456.5 missense
NM_004456.5 missense
Scores
7
8
1
Clinical Significance
Conservation
PhyloP100: 7.61
Genes affected
EZH2 (HGNC:3527): (enhancer of zeste 2 polycomb repressive complex 2 subunit) This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein associates with the embryonic ectoderm development protein, the VAV1 oncoprotein, and the X-linked nuclear protein. This protein may play a role in the hematopoietic and central nervous systems. Multiple alternatively splcied transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Feb 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004456.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr7-148807667-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 975993.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, EZH2
PP5
?
Variant 7-148807669-C-T is Pathogenic according to our data. Variant chr7-148807669-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148807669-C-T is described in Lovd as [Pathogenic]. Variant chr7-148807669-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EZH2 | NM_004456.5 | c.2233G>A | p.Glu745Lys | missense_variant | 20/20 | ENST00000320356.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EZH2 | ENST00000320356.7 | c.2233G>A | p.Glu745Lys | missense_variant | 20/20 | 1 | NM_004456.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1445944Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 717420
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1445944
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
717420
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Weaver syndrome Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 745 of the EZH2 protein (p.Glu745Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Weaver syndrome (PMID: 22190405, 23239504, 24214728, 29620724). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 65675). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EZH2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects EZH2 function (PMID: 26694085). For these reasons, this variant has been classified as Pathogenic. - |
EZH2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 09, 2023 | The EZH2 c.2233G>A variant is predicted to result in the amino acid substitution p.Glu745Lys. This variant has been reported in three individuals with EZH2-related phenotpes; in two of the subjects, this variant was found to be de novo (Tatton-Brown et al 2011. PubMed ID: 22190405; Al-Salem A et al 2012. PubMed ID: 23239504; Maddirevula S et al 2018. PubMed ID: 29620724, Table S6). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
P;B;P;B;P;P
Vest4
MutPred
0.47
.;Gain of ubiquitination at E740 (P = 0.009);.;.;.;.;
MVP
MPC
1.7
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at