7-148807681-A-G

Position:

• chr7-148807681-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_004456.5(EZH2):​c.2221T>C​(p.Tyr741His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y741C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: EZH2 NM_004456.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.97

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004456.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-148807680-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, EZH2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 7-148807681-A-G is Pathogenic according to our data. Variant chr7-148807681-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421581.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.2221T>C	p.Tyr741His	missense_variant	20/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.2221T>C	p.Tyr741His	missense_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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 20, 2016

The Y741H variant has not been published as a pathogenic variant, nor has it been reported as a benign variantto our knowledge. A different missense change at this position (Y741C) has been reportedpreviously as a de novo variant in an individual with increased height, increased occipito-frontalcircumference, round face, hypertelorism, high broad forehead, and high hairline (Tatton-Brown etal., 2011). The Y741H variant was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The Y741H variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ inpolarity, charge, size, and/or other properties. This substitution occurs at a position that isconserved across species, and in silico analysis predicts this variant is probably damaging to theprotein structure/function. Therefore, this variant is likely pathogenic; however, the possibilitythat it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.75
MutPred		0.50		.;Gain of disorder (P = 0.033);.;.;.;.;
MVP		0.91
MPC		2.8
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064795225; hg19: chr7-148504773;