7-148807704-T-TATCTGAAACAAC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_004456.5(EZH2):c.2197_2198insGTTGTTTCAGAT(p.Arg732_Tyr733insCysCysPheArg) variant causes a inframe insertion, splice region 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y733Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: EZH2 NM_004456.5 inframe_insertion, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004456.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 7-148807704-T-TATCTGAAACAAC is Pathogenic according to our data. Variant chr7-148807704-T-TATCTGAAACAAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 643660.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.2197_2198insGTTGTTTCAGAT	p.Arg732_Tyr733insCysCysPheArg	inframe_insertion, splice_region_variant	20/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.2197_2198insGTTGTTTCAGAT	p.Arg732_Tyr733insCysCysPheArg	inframe_insertion, splice_region_variant	20/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weaver syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2018

This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of Weaver syndrome (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have not been reported for this variant. If the canonical splice site is maintained and the duplicated sequence is translated, then this variant is expected to result in an in-frame insertion, for which experimental studies and prediction algorithms are not available. However, if the canonical splice site is not used, alternative splicing using the newly created splice site would likely have no effect on the translated protein. This sequence change duplicates 12 nucleotides across the intron 19/exon 20 boundary of the EZH2 gene, including part of the canonical splice site. It is expected to either cause an in-frame insertion at p.Arg732 (p.Arg732_Tyr733insCysCysPheArg) or to have no protein effect, due to utilization of a newly created alternate splice site. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1584844589; hg19: chr7-148504796;