Genetic Variant EZH2:c.*120T>A (chr7-148807526-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004456.5(EZH2):c.*120T>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00000154 in 648,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

EZH2
NM_004456.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.08

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

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	Effect	Exon Rank	Protein	UniProt
EZH2	NM_004456.5	MANE Select	c.*120T>A	3_prime_UTR	Exon 20 of 20	NP_004447.2
EZH2	NM_001203247.2		c.*120T>A	3_prime_UTR	Exon 20 of 20	NP_001190176.1	Q15910-1
EZH2	NM_001203248.2		c.*120T>A	3_prime_UTR	Exon 20 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EZH2	ENST00000320356.7	TSL:1 MANE Select	c.*120T>A	3_prime_UTR	Exon 20 of 20	ENSP00000320147.2	Q15910-2
EZH2	ENST00000460911.5	TSL:1	c.*120T>A	3_prime_UTR	Exon 20 of 20	ENSP00000419711.1	Q15910-1
EZH2	ENST00000350995.6	TSL:1	c.*120T>A	3_prime_UTR	Exon 19 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000154

AC:

AN:

648038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

338674

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16956

American (AMR)

AF:

0.00

AC:

AN:

31480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18722

East Asian (EAS)

AF:

0.00

AC:

AN:

32022

South Asian (SAS)

AF:

0.00

AC:

AN:

58114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2972

European-Non Finnish (NFE)

AF:

0.00000245

AC:

AN:

408706

Other (OTH)

AF:

0.00

AC:

AN:

32846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over