rs2302427

chr7-148828812-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004456.5(EZH2):c.553G>C(p.Asp185His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0737 in 1,612,676 control chromosomes in the GnomAD database, including 4,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D185D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.062 (394 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4546 hom.)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 7.28

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EZH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00156039).
• BP6: Variant 7-148828812-C-G is Benign according to our data. Variant chr7-148828812-C-G is described in ClinVar as [Benign]. Clinvar id is 134224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148828812-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.553G>C	p.Asp185His	missense_variant	6/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.553G>C	p.Asp185His	missense_variant	6/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9447 AN: 151914 Hom.: 396 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0510

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.0942

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0733

GnomAD3 exomes AF: 0.0783 AC: 19436 AN: 248352 Hom.: 990 AF XY: 0.0802 AC XY: 10781 AN XY: 134452

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0359

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.176

Gnomad SAS exome AF: 0.0716

Gnomad FIN exome AF: 0.0973

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.0805

GnomAD4 exome AF: 0.0749 AC: 109369 AN: 1460644 Hom.: 4546 Cov.: 31 AF XY: 0.0752 AC XY: 54645 AN XY: 726566

Gnomad4 AFR exome AF: 0.0120

Gnomad4 AMR exome AF: 0.0368

Gnomad4 ASJ exome AF: 0.0999

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0716

Gnomad4 FIN exome AF: 0.0959

Gnomad4 NFE exome AF: 0.0749

Gnomad4 OTH exome AF: 0.0811

GnomAD4 genome AF: 0.0621 AC: 9439 AN: 152032 Hom.: 394 Cov.: 32 AF XY: 0.0641 AC XY: 4759 AN XY: 74288

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0509

Gnomad4 ASJ AF: 0.0948

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.0818

Gnomad4 FIN AF: 0.0942

Gnomad4 NFE AF: 0.0773

Gnomad4 OTH AF: 0.0735

Alfa AF: 0.0756 Hom.: 300

Bravo AF: 0.0579

TwinsUK AF: 0.0698 AC: 259

ALSPAC AF: 0.0680 AC: 262

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.0836 AC: 719

ExAC AF: 0.0783 AC: 9506

Asia WGS AF: 0.127 AC: 443 AN: 3478

EpiCase AF: 0.0859

EpiControl AF: 0.0846

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Weaver syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.0016	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	0.0000036	P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D;D
Polyphen		0.35	B;B;P;P;B;B
Vest4		0.15
MPC		1.9
ClinPred		0.034	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.28

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: rs2302427; hg19: chr7-148525904; COSMIC: COSV57449162;