chr7-148811696-C-T

Position:

• chr7-148811696-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000320356.7(EZH2):​c.1876G>A​(p.Val626Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EZH2 ENST00000320356.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.62

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a strand (size 10) in uniprot entity EZH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000320356.7
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EZH2. . Gene score misZ 4.6808 (greater than the threshold 3.09). Trascript score misZ 5.1095 (greater than threshold 3.09). GenCC has associacion of gene with Weaver syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 7-148811696-C-T is Pathogenic according to our data. Variant chr7-148811696-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811696-C-T is described in Lovd as [Pathogenic]. Variant chr7-148811696-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH2	NM_004456.5	c.1876G>A	p.Val626Met	missense_variant	16/20	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.1876G>A	p.Val626Met	missense_variant	16/20	1	NM_004456.5	ENSP00000320147	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726748

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weaver syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center	-	This is a de novo variant in EZH2. The patient's phenotype fits perfectly with Weaver Syndrome with tall stature and advanced bone age. This same variant is already in ClinVar in another patient with Weaver Syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 30, 2021	- -

EZH2-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Pathogenic and reported on 12-04-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N;D;D;N;N;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.93
MutPred		0.56		.;Loss of catalytic residue at V621 (P = 0.1444);.;.;.;.;
MVP		0.98
MPC		2.5
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.88
gMVP		0.72

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: rs587783625; hg19: chr7-148508788; COSMIC: COSV57451459;