rs78589034

chr7-148811726-G-Achr7-148811726-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004456.5(EZH2):c.1852-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,609,406 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: EZH2 NM_004456.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007363
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-148811726-G-A is Benign according to our data. Variant chr7-148811726-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148811726-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (301/152228) while in subpopulation NFE AF= 0.00335 (228/68012). AF 95% confidence interval is 0.003. There are 3 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.1852-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.1852-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004456.5	P4

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152110 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00192 AC: 474 AN: 247292 Hom.: 2 AF XY: 0.00206 AC XY: 276 AN XY: 134204

Gnomad AFR exome AF: 0.000373

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00298 AC: 4338 AN: 1457178 Hom.: 6 Cov.: 29 AF XY: 0.00292 AC XY: 2117 AN XY: 725196

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152228 Hom.: 3 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74436

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000755

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00281 Hom.: 2

Bravo AF: 0.00173

EpiCase AF: 0.00262

EpiControl AF: 0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EZH2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	This variant is associated with the following publications: (PMID: 26917488) -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 02, 2015	- -

Weaver syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.3
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000074
dbscSNV1_RF	Benign	0.0060
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: rs78589034; hg19: chr7-148508818; COSMIC: COSV57448954;