7-148826616-C-T

Variant names:

• chr7-148826616-C-T
• rs1057520183
• NM_004456.5:c.745G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004456.5(EZH2):​c.745G>A​(p.Glu249Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.62
• Publications: 16 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.745G>A	p.Glu249Lys	missense	Exon 8 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.745G>A	p.Glu249Lys	missense	Exon 8 of 20	NP_001190176.1
	EZH2	NM_001203248.2		c.718G>A	p.Glu240Lys	missense	Exon 8 of 20	NP_001190177.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.745G>A	p.Glu249Lys	missense	Exon 8 of 20	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.745G>A	p.Glu249Lys	missense	Exon 8 of 20	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.628G>A	p.Glu210Lys	missense	Exon 7 of 19	ENSP00000223193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1382076 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 685250

African (AFR) AF: 0.00 AC: 0 AN: 31288

American (AMR) AF: 0.00 AC: 0 AN: 35988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38170

South Asian (SAS) AF: 0.00 AC: 0 AN: 70940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069952

Other (OTH) AF: 0.00 AC: 0 AN: 56342

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.98	D
Vest4		0.85
MutPred		0.22		Gain of ubiquitination at E249 (P = 0.0037)
MVP		0.84
MPC		2.6
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.59
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1057520183; hg19: chr7-148523708; COSMIC: COSV57446770;