rs61732845

chr7-148829816-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004456.5(EZH2):c.396T>C(p.Pro132=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,596,652 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (35 hom.)
• Consequence: EZH2 NM_004456.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.881

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 7-148829816-A-G is Benign according to our data. Variant chr7-148829816-A-G is described in ClinVar as [Benign]. Clinvar id is 359286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.881 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0045 (686/152282) while in subpopulation NFE AF= 0.00594 (404/68016). AF 95% confidence interval is 0.00546. There are 5 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 686 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.396T>C	p.Pro132=	synonymous_variant	5/20	ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.396T>C	p.Pro132=	synonymous_variant	5/20	1	NM_004456.5	P4

Frequencies

GnomAD3 genomes AF: 0.00451 AC: 686 AN: 152164 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00525 AC: 1275 AN: 242642 Hom.: 9 AF XY: 0.00530 AC XY: 694 AN XY: 130968

Gnomad AFR exome AF: 0.000687

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00243

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00656

Gnomad OTH exome AF: 0.00741

GnomAD4 exome AF: 0.00588 AC: 8495 AN: 1444370 Hom.: 35 Cov.: 27 AF XY: 0.00585 AC XY: 4203 AN XY: 718682

Gnomad4 AFR exome AF: 0.00104

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152282 Hom.: 5 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74476

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00596 Hom.: 0

Bravo AF: 0.00458

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EZH2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

EZH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Weaver syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	8.3
Dann	Benign	0.57

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: rs61732845; hg19: chr7-148526908; COSMIC: COSV57453396;