7-148826513-G-A

Variant names:

• chr7-148826513-G-A
• rs587778304
• NM_004456.5:c.848C>T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_004456.5(EZH2):​c.848C>T​(p.Thr283Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.63

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a helix (size 10) in uniprot entity EZH2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004456.5
• 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.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.848C>T	p.Thr283Met	missense_variant	Exon 8 of 20	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.848C>T	p.Thr283Met	missense_variant	Exon 8 of 20	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1453058 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722842

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000813

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	.;M;.;M;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.043	D;D;D;D;D;D
Polyphen		0.93	P;D;D;D;P;D
Vest4		0.61
MutPred		0.36		.;Gain of helix (P = 0.0696);.;Gain of helix (P = 0.0696);.;.;
MVP		0.91
MPC		2.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs587778304; hg19: chr7-148523605; COSMIC: COSV57450042;