chr7-148807624-AG-A

Variant names:

• chr7-148807624-AG-A
• rs3217095
• NM_004456.5:c.*21delC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004456.5(EZH2):​c.*21delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.75 (44114 hom., cov: 0)
  • Exomes 𝑓: 0.69 (339386 hom.)
• Consequence: EZH2 NM_004456.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0530
• Publications: 14 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.*21delC		3_prime_UTR_variant	Exon 20 of 20	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.*21delC		3_prime_UTR_variant	Exon 20 of 20	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114217 AN: 151728 Hom.: 44056 Cov.: 0

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.706

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.736

GnomAD2 exomes AF: 0.685 AC: 140510 AN: 205250 AF XY: 0.677

Gnomad AFR exome AF: 0.934

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.678

Gnomad EAS exome AF: 0.648

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.670

Gnomad OTH exome AF: 0.683

GnomAD4 exome AF: 0.688 AC: 980410 AN: 1425804 Hom.: 339386 Cov.: 0 AF XY: 0.687 AC XY: 485109 AN XY: 706560

African (AFR) AF: 0.946 AC: 31055 AN: 32812

American (AMR) AF: 0.724 AC: 29304 AN: 40468

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 17394 AN: 25460

East Asian (EAS) AF: 0.655 AC: 25445 AN: 38862

South Asian (SAS) AF: 0.676 AC: 55336 AN: 81892

European-Finnish (FIN) AF: 0.608 AC: 31356 AN: 51586

Middle Eastern (MID) AF: 0.754 AC: 4299 AN: 5702

European-Non Finnish (NFE) AF: 0.684 AC: 745110 AN: 1089974

Other (OTH) AF: 0.696 AC: 41111 AN: 59048

GnomAD4 genome AF: 0.753 AC: 114337 AN: 151846 Hom.: 44114 Cov.: 0 AF XY: 0.749 AC XY: 55535 AN XY: 74158

African (AFR) AF: 0.936 AC: 38801 AN: 41436

American (AMR) AF: 0.749 AC: 11437 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2350 AN: 3464

East Asian (EAS) AF: 0.670 AC: 3447 AN: 5142

South Asian (SAS) AF: 0.670 AC: 3211 AN: 4790

European-Finnish (FIN) AF: 0.586 AC: 6167 AN: 10520

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46502 AN: 67916

Other (OTH) AF: 0.736 AC: 1552 AN: 2108

Alfa AF: 0.714 Hom.: 7112

Bravo AF: 0.774

Asia WGS AF: 0.694 AC: 2414 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Weaver syndrome Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.053
Mutation Taster		=100/0	polymorphism (auto)

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: rs3217095; hg19: chr7-148504716; COSMIC: COSV57445842; COSMIC: COSV57445842;