Genetic Variant EZH2:p.Ser519Thr (chr7-148815031-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_004456.5(EZH2):c.1555T>A(p.Ser519Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.89

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain CXC (size 102) in uniprot entity EZH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004456.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the EZH2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 38 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.6808 (above the threshold of 3.09). Trascript score misZ: 5.1095 (above the threshold of 3.09). GenCC associations: The gene is linked to Weaver syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.36852628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5 link	c.1555T>A	p.Ser519Thr	missense_variant	Exon 14 of 20	ENST00000320356.7	NP_004447.2	Q15910-2A0A090N8E9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7 link	c.1555T>A	p.Ser519Thr	missense_variant	Exon 14 of 20	1	NM_004456.5	ENSP00000320147.2		Q15910-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251064

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.4

N;N;N;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.90

P;P;D;P

Vest4

0.52

MutPred

0.32

Gain of glycosylation at S514 (P = 0.1056);.;.;.;

MVP

0.91

MPC

1.2

ClinPred

0.67

GERP RS

5.3

Varity_R

0.49

gMVP

0.59

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over