rs1057520183

Variant names:

• chr7-148826616-C-A
• rs1057520183
• NM_004456.5:c.745G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-148826616-C-A
• chr7-148826616-C-G
• chr7-148826616-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004456.5(EZH2):​c.745G>T​(p.Glu249*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,382,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: EZH2 NM_004456.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.745G>T	p.Glu249*	stop_gained	Exon 8 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.745G>T	p.Glu249*	stop_gained	Exon 8 of 20	NP_001190176.1
	EZH2	NM_001203248.2		c.718G>T	p.Glu240*	stop_gained	Exon 8 of 20	NP_001190177.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.745G>T	p.Glu249*	stop_gained	Exon 8 of 20	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.745G>T	p.Glu249*	stop_gained	Exon 8 of 20	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.628G>T	p.Glu210*	stop_gained	Exon 7 of 19	ENSP00000223193.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1382076 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 685250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31288

American (AMR) AF: 0.00 AC: 0 AN: 35988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38170

South Asian (SAS) AF: 0.00 AC: 0 AN: 70940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069952

Other (OTH) AF: 0.00 AC: 0 AN: 56342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.94
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1057520183; hg19: chr7-148523708;