rs557474218

Positions:

• chr7-148832759-G-GA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000320356.7(EZH2):​c.247-10_247-9insT variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,555,412 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (19 hom.)
• Consequence: EZH2 ENST00000320356.7 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79

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 -16 ACMG points.

• BP6: Variant 7-148832759-G-GA is Benign according to our data. Variant chr7-148832759-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 239931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00295 (448/151972) while in subpopulation NFE AF= 0.0048 (326/67924). AF 95% confidence interval is 0.00437. There are 0 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 448 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH2	NM_004456.5	c.247-10_247-9insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.247-10_247-9insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004456.5	ENSP00000320147	P4

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 151854 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00286 AC: 691 AN: 241264 Hom.: 1 AF XY: 0.00287 AC XY: 376 AN XY: 130924

Gnomad AFR exome AF: 0.000564

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000749

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.000205

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00419 AC: 5887 AN: 1403440 Hom.: 19 Cov.: 22 AF XY: 0.00406 AC XY: 2843 AN XY: 700048

Gnomad4 AFR exome AF: 0.000662

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000144

Gnomad4 FIN exome AF: 0.000796

Gnomad4 NFE exome AF: 0.00512

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00295 AC: 448 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74286

Gnomad4 AFR AF: 0.000868

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00480

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Weaver syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

EZH2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

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: rs557474218; hg19: chr7-148529851;