Genetic Variant EZH2:p.Ile744Met (chr7-148807670-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_004456.5(EZH2):c.2232C>G(p.Ile744Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I744I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.195

Publications

0 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

EZH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004456.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

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	UniProt
EZH2	NM_004456.5	MANE Select	c.2232C>G	p.Ile744Met	missense	Exon 20 of 20	NP_004447.2
EZH2	NM_001203247.2		c.2217C>G	p.Ile739Met	missense	Exon 20 of 20	NP_001190176.1	Q15910-1
EZH2	NM_001203248.2		c.2190C>G	p.Ile730Met	missense	Exon 20 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2232C>G	p.Ile744Met	missense	Exon 20 of 20	ENSP00000320147.2	Q15910-2
EZH2	ENST00000460911.5	TSL:1	c.2217C>G	p.Ile739Met	missense	Exon 20 of 20	ENSP00000419711.1	Q15910-1
EZH2	ENST00000350995.6	TSL:1	c.2100C>G	p.Ile700Met	missense	Exon 19 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

0.00091

Eigen_PC

Benign

-0.097

FATHMM_MKL

Uncertain

0.76

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.9

PhyloP100

0.20

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.77

MutPred

0.33

Gain of disorder (P = 0.0606)

MVP

0.95

MPC

2.5

ClinPred

0.98

GERP RS

-1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.95

Mutation Taster

=44/56

disease causing

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over