rs1200905474

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The ENST00000320356.7(EZH2):​c.1178C>T​(p.Thr393Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,778 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T393T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

EZH2
ENST00000320356.7 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.41
Variant links:
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 Likely_benign. Variant got -5 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EZH2. . Gene score misZ 4.6808 (greater than the threshold 3.09). Trascript score misZ 5.1095 (greater than threshold 3.09). GenCC has associacion of gene with Weaver syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.16849318).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EZH2NM_004456.5 linkuse as main transcriptc.1178C>T p.Thr393Met missense_variant 10/20 ENST00000320356.7 NP_004447.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EZH2ENST00000320356.7 linkuse as main transcriptc.1178C>T p.Thr393Met missense_variant 10/201 NM_004456.5 ENSP00000320147 P4Q15910-2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151914
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251370
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151914
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

Weaver syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 25, 2023In 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 528797). This variant has not been reported in the literature in individuals affected with EZH2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 393 of the EZH2 protein (p.Thr393Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.097
.;T;.;.;.;.
Eigen
Benign
-0.038
Eigen_PC
Benign
0.12
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
.;D;D;D;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.17
T;T;T;T;T;T
MetaSVM
Benign
-0.39
T
MutationAssessor
Benign
-0.14
.;N;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.0
N;N;N;N;N;N
REVEL
Uncertain
0.30
Sift
Benign
0.096
T;T;T;T;T;T
Sift4G
Benign
0.13
T;T;T;T;T;T
Polyphen
0.48
P;P;P;P;P;B
Vest4
0.41
MVP
0.60
MPC
2.5
ClinPred
0.65
D
GERP RS
5.7
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.7
Varity_R
0.082
gMVP
0.32

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

LitVar

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

Other links and lift over

dbSNP: rs1200905474; hg19: chr7-148515031; API