Variant rs775407864 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_004456.5(EZH2):c.149T>C(p.Leu50Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000751 in 1,612,242 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 5.37

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]

EZH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant where missense usually causes diseases, EZH2

BP4

Computational evidence support a benign effect (MetaRNN=0.34399158).

BS2

High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5 linkuse as main transcript	c.149T>C	p.Leu50Ser	missense_variant	3/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7 linkuse as main transcript	c.149T>C	p.Leu50Ser	missense_variant	3/20	1	NM_004456.5	P4	Q15910-2

Frequencies

GnomAD3 genomes

AF:

0.0000730

AC:

AN:

150732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000267

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:

0.0000884

Gnomad OTH

AF:

0.000486

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251104

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000730

AC:

AN:

150732

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

73522

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000267

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.000486

Alfa

AF:

0.0000762

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Weaver syndrome

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 19, 2023	- -
Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

-0.070

Cadd

Uncertain

Dann

Benign

0.90

Eigen

Benign

-0.16

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.34

T;T;T;T;T;T

MetaSVM

Uncertain

-0.0030

MutationAssessor

Benign

0.0

N;N;N;N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.10

N;N;N;N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.75

T;T;T;T;T;T

Sift4G

Benign

0.78

T;T;T;T;T;T

Polyphen

0.0020

B;B;B;B;B;B

Vest4

0.63

MVP

0.80

MPC

1.7

ClinPred

0.89

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.57

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over