NM_004456.5:c.1555T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004456.5(EZH2):c.1555T>C(p.Ser519Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

EZH2
NM_004456.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 8.89

Publications

6 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

EZH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 7-148815031-A-G is Benign according to our data. Variant chr7-148815031-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 359279.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000263 (4/152214) while in subpopulation NFE AF = 0.0000588 (4/68036). AF 95% confidence interval is 0.0000197. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EZH2	NM_004456.5	MANE Select	c.1555T>C	p.Ser519Pro	missense	Exon 14 of 20	NP_004447.2
EZH2	NM_001203247.2		c.1540T>C	p.Ser514Pro	missense	Exon 14 of 20	NP_001190176.1	Q15910-1
EZH2	NM_001203248.2		c.1513T>C	p.Ser505Pro	missense	Exon 14 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EZH2	ENST00000320356.7	TSL:1 MANE Select	c.1555T>C	p.Ser519Pro	missense	Exon 14 of 20	ENSP00000320147.2	Q15910-2
EZH2	ENST00000460911.5	TSL:1	c.1540T>C	p.Ser514Pro	missense	Exon 14 of 20	ENSP00000419711.1	Q15910-1
EZH2	ENST00000350995.6	TSL:1	c.1423T>C	p.Ser475Pro	missense	Exon 13 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

251064

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111868

Other (OTH)

AF:

0.0000497

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000263

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000675

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

EZH2-related disorder (1)

Inborn genetic diseases (1)

Weaver syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.55

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

PhyloP100

8.9

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.77

Sift

Uncertain

0.025

Sift4G

Uncertain

0.026

Polyphen

0.026

Vest4

0.73

MutPred

0.38

Loss of MoRF binding (P = 0.0729)

MVP

0.91

MPC

2.5

ClinPred

0.84

GERP RS

5.3

Varity_R

0.79

gMVP

0.77

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over