chr7-148828796-CCATCATCATCAT-C

Variant names:

• chr7-148828796-CCATCATCATCAT-C
• rs587778303
• NM_004456.5:c.557_568delATGATGATGATG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP3

The NM_004456.5(EZH2):​c.557_568delATGATGATGATG​(p.Asp186_Asp189del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EZH2 NM_004456.5 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.72
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

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

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP3: Nonframeshift variant in repetitive region in NM_004456.5

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.557_568delATGATGATGATG	p.Asp186_Asp189del	disruptive_inframe_deletion	Exon 6 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.557_568delATGATGATGATG	p.Asp186_Asp189del	disruptive_inframe_deletion	Exon 6 of 20	NP_001190176.1
	EZH2	NM_001203248.2		c.530_541delATGATGATGATG	p.Asp177_Asp180del	disruptive_inframe_deletion	Exon 6 of 20	NP_001190177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.557_568delATGATGATGATG	p.Asp186_Asp189del	disruptive_inframe_deletion	Exon 6 of 20	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.557_568delATGATGATGATG	p.Asp186_Asp189del	disruptive_inframe_deletion	Exon 6 of 20	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.440_451delATGATGATGATG	p.Asp147_Asp150del	disruptive_inframe_deletion	Exon 5 of 19	ENSP00000223193.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=33/167	disease causing

Splicing

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

Other links and lift over

dbSNP: rs587778303; hg19: chr7-148525888;