7-148828796-CCATCATCATCAT-CCATCATCAT

Variant names:

• chr7-148828796-CCAT-C
• rs587778303
• NM_004456.5:c.566_568delATG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_004456.5(EZH2):​c.566_568delATG​(p.Asp189del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000366 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: EZH2 NM_004456.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.70
• 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: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_004456.5
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000789 (12/152036) while in subpopulation SAS AF = 0.000417 (2/4792). AF 95% confidence interval is 0.00013. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 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.566_568delATG	p.Asp189del	disruptive_inframe_deletion	Exon 6 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.566_568delATG	p.Asp189del	disruptive_inframe_deletion	Exon 6 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.539_541delATG	p.Asp180del	disruptive_inframe_deletion	Exon 6 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.566_568delATG	p.Asp189del	disruptive_inframe_deletion	Exon 6 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.566_568delATG	p.Asp189del	disruptive_inframe_deletion	Exon 6 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.449_451delATG	p.Asp150del	disruptive_inframe_deletion	Exon 5 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151918 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000643 AC: 16 AN: 248664 AF XY: 0.0000520

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461304 Hom.: 0 AF XY: 0.0000358 AC XY: 26 AN XY: 726958

African (AFR) AF: 0.000269 AC: 9 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111660

Other (OTH) AF: 0.0000828 AC: 5 AN: 60374

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74302

African (AFR) AF: 0.000241 AC: 10 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Weaver syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=36/64	disease causing

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: rs587778303; hg19: chr7-148525888;