rs587778304

Variant names:

• chr7-148826513-G-A
• rs587778304
• NM_004456.5:c.848C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-148826513-G-A
• chr7-148826513-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_004456.5(EZH2):​c.848C>T​(p.Thr283Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,453,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 9.63
• Publications: 2 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.848C>T	p.Thr283Met	missense	Exon 8 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.848C>T	p.Thr283Met	missense	Exon 8 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.821C>T	p.Thr274Met	missense	Exon 8 of 20	NP_001190177.1	Q15910-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.848C>T	p.Thr283Met	missense	Exon 8 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.848C>T	p.Thr283Met	missense	Exon 8 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.731C>T	p.Thr244Met	missense	Exon 7 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000619 AC: 9 AN: 1453058 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722842

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 84730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000813 AC: 9 AN: 1106594

Other (OTH) AF: 0.00 AC: 0 AN: 59900

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.043	D
Polyphen		0.93	P
Vest4		0.61
MutPred		0.36		Gain of helix (P = 0.0696)
MVP		0.91
MPC		2.4
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.74
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs587778304; hg19: chr7-148523605;