7-148809304-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004456.5(EZH2):c.2110+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,600,172 control chromosomes in the GnomAD database, including 3,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 290 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2967 hom. )

Consequence

EZH2
NM_004456.5 splice_region, intron

Scores

Splicing: ADA: 0.0003168

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.791

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

Weaver syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

EZH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 7-148809304-A-C is Benign according to our data. Variant chr7-148809304-A-C is described in ClinVar as Benign. ClinVar VariationId is 137273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5 link	c.2110+6T>G		splice_region_variant, intron_variant	Intron 18 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.2110+6T>G		splice_region_variant, intron_variant	Intron 18 of 19	1	NM_004456.5	ENSP00000320147.2		Q15910-2

Frequencies

GnomAD3 genomes

AF:

0.0503

AC:

7661

AN:

152232

Hom.:

286

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0192

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.0571

Gnomad EAS

AF:

0.0373

Gnomad SAS

AF:

0.0457

Gnomad FIN

AF:

0.0662

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.0547

Gnomad OTH

AF:

0.0545

GnomAD2 exomes

AF:

0.0682

AC:

17153

AN:

251348

AF XY:

0.0651

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.182

Gnomad ASJ exome

AF:

0.0587

Gnomad EAS exome

AF:

0.0360

Gnomad FIN exome

AF:

0.0690

Gnomad NFE exome

AF:

0.0526

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0576

AC:

83363

AN:

1447822

Hom.:

2967

Cov.:

AF XY:

0.0571

AC XY:

40944

AN XY:

716946

show subpopulations

African (AFR)

AF:

0.0174

AC:

580

AN:

33298

American (AMR)

AF:

0.173

AC:

7704

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

1559

AN:

26040

East Asian (EAS)

AF:

0.0526

AC:

2066

AN:

39284

South Asian (SAS)

AF:

0.0459

AC:

3948

AN:

85962

European-Finnish (FIN)

AF:

0.0665

AC:

3542

AN:

53290

Middle Eastern (MID)

AF:

0.0826

AC:

474

AN:

5738

European-Non Finnish (NFE)

AF:

0.0546

AC:

60068

AN:

1099912

Other (OTH)

AF:

0.0573

AC:

3422

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

3537

7074

10612

14149

17686

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2330

4660

6990

9320

11650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0503

AC:

7663

AN:

152350

Hom.:

290

Cov.:

AF XY:

0.0511

AC XY:

3805

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0191

AC:

794

AN:

41582

American (AMR)

AF:

0.109

AC:

1666

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0571

AC:

198

AN:

3470

East Asian (EAS)

AF:

0.0370

AC:

192

AN:

5192

South Asian (SAS)

AF:

0.0456

AC:

220

AN:

4828

European-Finnish (FIN)

AF:

0.0662

AC:

703

AN:

10616

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0547

AC:

3721

AN:

68036

Other (OTH)

AF:

0.0539

AC:

114

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

374

749

1123

1498

1872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0556

Hom.:

222

Bravo

AF:

0.0552

Asia WGS

AF:

0.0570

AC:

199

AN:

3478

EpiCase

AF:

0.0579

EpiControl

AF:

0.0561

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 07, 2014

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. -

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Weaver syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.040

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over