Genetic Variant EZH2:c.1852-21T>C (chr7-148811741-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004456.5(EZH2):c.1852-21T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,595,956 control chromosomes in the GnomAD database, including 355,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.67 ( 34810 hom., cov: 31)

Exomes 𝑓: 0.67 ( 320846 hom. )

Consequence

EZH2
NM_004456.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.352

Variant links:

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]

EZH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 7-148811741-A-G is Benign according to our data. Variant chr7-148811741-A-G is described in ClinVar as [Benign]. Clinvar id is 670472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811741-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5 link	c.1852-21T>C		intron_variant	Intron 15 of 19	ENST00000320356.7	NP_004447.2	Q15910-2A0A090N8E9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7 link	c.1852-21T>C		intron_variant	Intron 15 of 19	1	NM_004456.5	ENSP00000320147.2		Q15910-2

Frequencies

GnomAD3 genomes

AF:

0.675

AC:

102472

AN:

151810

Hom.:

34787

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.586

Gnomad AMR

AF:

0.724

Gnomad ASJ

AF:

0.675

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.564

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.666

Gnomad OTH

AF:

0.677

GnomAD3 exomes

AF:

0.669

AC:

162544

AN:

243020

Hom.:

54502

AF XY:

0.664

AC XY:

87729

AN XY:

132162

show subpopulations

Gnomad AFR exome

AF:

0.707

Gnomad AMR exome

AF:

0.728

Gnomad ASJ exome

AF:

0.679

Gnomad EAS exome

AF:

0.668

Gnomad SAS exome

AF:

0.615

Gnomad FIN exome

AF:

0.590

Gnomad NFE exome

AF:

0.671

Gnomad OTH exome

AF:

0.663

GnomAD4 exome

AF:

0.666

AC:

961145

AN:

1444028

Hom.:

320846

Cov.:

AF XY:

0.664

AC XY:

477616

AN XY:

719260

show subpopulations

Gnomad4 AFR exome

AF:

0.717

Gnomad4 AMR exome

AF:

0.728

Gnomad4 ASJ exome

AF:

0.682

Gnomad4 EAS exome

AF:

0.660

Gnomad4 SAS exome

AF:

0.619

Gnomad4 FIN exome

AF:

0.591

Gnomad4 NFE exome

AF:

0.668

Gnomad4 OTH exome

AF:

0.662

GnomAD4 genome

AF:

0.675

AC:

102549

AN:

151928

Hom.:

34810

Cov.:

AF XY:

0.671

AC XY:

49866

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.709

Gnomad4 AMR

AF:

0.725

Gnomad4 ASJ

AF:

0.675

Gnomad4 EAS

AF:

0.672

Gnomad4 SAS

AF:

0.614

Gnomad4 FIN

AF:

0.564

Gnomad4 NFE

AF:

0.666

Gnomad4 OTH

AF:

0.679

Alfa

AF:

0.668

Hom.:

7360

Bravo

AF:

0.692

Asia WGS

AF:

0.657

AC:

2286

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Weaver syndrome

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.46

DANN

Benign

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over