7-148807667-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_004456.5(EZH2):c.2235A>T(p.Glu745Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E745K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.221

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-148807669-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, EZH2
• PP5: Variant 7-148807667-T-A is Pathogenic according to our data. Variant chr7-148807667-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 975993.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.2235A>T	p.Glu745Asp	missense_variant	20/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.2235A>T	p.Glu745Asp	missense_variant	20/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weaver syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 26, 2019

This variant was identified as de novo (maternity and paternity confirmed). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.97	D;P;D;B;D;D
Vest4		0.88
MutPred		0.32		.;Loss of methylation at K735 (P = 0.1228);.;.;.;.;
MVP		0.99
MPC		2.2
ClinPred		0.96	D
GERP RS		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs1563181538; hg19: chr7-148504759;