chr7-148807371-T-C

Variant names:

• chr7-148807371-T-C
• rs543537882
• ENST00000683292.1:n.*1427A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000683292.1(EZH2):​n.*1427A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 446,710 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: EZH2 ENST00000683292.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0160
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00154 (235/152336) while in subpopulation AFR AF = 0.00515 (214/41580). AF 95% confidence interval is 0.00458. There are 3 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 235 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.*275A>G		downstream_gene_variant		ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.*275A>G		downstream_gene_variant		1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000173 AC: 51 AN: 294374 Hom.: 0 Cov.: 0 AF XY: 0.000112 AC XY: 17 AN XY: 151852

African (AFR) AF: 0.00370 AC: 35 AN: 9466

American (AMR) AF: 0.000702 AC: 8 AN: 11404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10140

East Asian (EAS) AF: 0.00 AC: 0 AN: 22638

South Asian (SAS) AF: 0.0000409 AC: 1 AN: 24436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1352

European-Non Finnish (NFE) AF: 0.0000111 AC: 2 AN: 180034

Other (OTH) AF: 0.000276 AC: 5 AN: 18122

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74504

African (AFR) AF: 0.00515 AC: 214 AN: 41580

American (AMR) AF: 0.00118 AC: 18 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00165

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Weaver syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.32
DANN	Benign	0.60
PhyloP100		0.016

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs543537882; hg19: chr7-148504463;