Genetic Variant EZH2:c.728+19G>C (chr7-148827145-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004456.5(EZH2):c.728+19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,597,520 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 4 hom. )

Consequence

EZH2
NM_004456.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.307

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 7-148827145-C-G is Benign according to our data. Variant chr7-148827145-C-G is described in ClinVar as [Benign]. Clinvar id is 259401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00515 (784/152258) while in subpopulation AFR AF= 0.0174 (723/41552). AF 95% confidence interval is 0.0163. There are 7 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 784 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5 link	c.728+19G>C		intron_variant	Intron 7 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.728+19G>C		intron_variant	Intron 7 of 19	1	NM_004456.5	ENSP00000320147.2		Q15910-2

Frequencies

GnomAD3 genomes

AF:

0.00513

AC:

780

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00151

AC:

371

AN:

245418

Hom.:

AF XY:

0.00107

AC XY:

142

AN XY:

132396

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000699

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000802

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.000622

AC:

899

AN:

1445262

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

378

AN XY:

719382

show subpopulations

Gnomad4 AFR exome

AF:

0.0183

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000356

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000169

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00515

AC:

784

AN:

152258

Hom.:

Cov.:

AF XY:

0.00485

AC XY:

361

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0174

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00593

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Weaver syndrome

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Mar 03, 2015

GeneDx

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

-0.73

CADD

Benign

DANN

Benign

0.71

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