rs587783625

Variant names:

• chr7-148811696-C-T
• rs587783625
• NM_004456.5:c.1876G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-148811696-C-T
• chr7-148811696-C-A
• chr7-148811696-C-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004456.5(EZH2):​c.1876G>A​(p.Val626Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.62
• Publications: 19 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 7-148811696-C-T is Pathogenic according to our data. Variant chr7-148811696-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 158579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1876G>A	p.Val626Met	missense	Exon 16 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.1861G>A	p.Val621Met	missense	Exon 16 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.1834G>A	p.Val612Met	missense	Exon 16 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.1876G>A	p.Val626Met	missense	Exon 16 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.1861G>A	p.Val621Met	missense	Exon 16 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.1744G>A	p.Val582Met	missense	Exon 15 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726748

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Weaver syndrome (4)
-	-	-	EZH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.56		Loss of catalytic residue at V621 (P = 0.1444)
MVP		0.98
MPC		2.5
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.88
gMVP		0.72
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587783625; hg19: chr7-148508788; COSMIC: COSV57451459;