Genetic Variant EZH2:p.Ser615Phe (chr7-148813966-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_004456.5(EZH2):c.1844C>T(p.Ser615Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S615P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 4.76

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Weaver syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

EZH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33516657).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EZH2	NM_004456.5	MANE Select	c.1844C>T	p.Ser615Phe	missense	Exon 15 of 20	NP_004447.2
EZH2	NM_001203247.2		c.1829C>T	p.Ser610Phe	missense	Exon 15 of 20	NP_001190176.1
EZH2	NM_001203248.2		c.1802C>T	p.Ser601Phe	missense	Exon 15 of 20	NP_001190177.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EZH2	ENST00000320356.7	TSL:1 MANE Select	c.1844C>T	p.Ser615Phe	missense	Exon 15 of 20	ENSP00000320147.2
EZH2	ENST00000460911.5	TSL:1	c.1829C>T	p.Ser610Phe	missense	Exon 15 of 20	ENSP00000419711.1
EZH2	ENST00000350995.6	TSL:1	c.1712C>T	p.Ser571Phe	missense	Exon 14 of 19	ENSP00000223193.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.073

Eigen

Benign

-0.032

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.064

MetaRNN

Benign

0.34

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.20

PhyloP100

4.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.47

REVEL

Uncertain

0.38

Sift

Benign

0.033

Sift4G

Benign

0.25

Polyphen

0.0070

Vest4

0.53

MutPred

0.54

Loss of disorder (P = 0.0057)

MVP

0.83

MPC

1.4

ClinPred

0.67

GERP RS

5.0

Varity_R

0.34

gMVP

0.51

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over