rs770006533

chr7-148816715-T-Achr7-148816715-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004456.5(EZH2):c.1474A>T(p.Thr492Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EZH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.23944777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.1474A>T	p.Thr492Ser	missense_variant	12/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.1474A>T	p.Thr492Ser	missense_variant	12/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135820

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weaver syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 16, 2016

This sequence change replaces threonine with serine at codon 492 of the EZH2 protein (p.Thr492Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs770006533, ExAC 0.002%) but has not been reported in the literature in individuals with a EZH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.090
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Benign	0.18	T;T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.31	B;B;B;D;B;B
Vest4		0.47
MutPred		0.26		.;Gain of MoRF binding (P = 0.1202);.;.;.;.;
MVP		0.76
MPC		1.2
ClinPred		0.68	D
GERP RS		5.1
Varity_R		0.27
gMVP		0.42

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

Other links and lift over

dbSNP: rs770006533; hg19: chr7-148513807;