rs10274701

Variant names:

• chr7-148855364-C-T
• rs10274701
• NM_004456.5:c.-7-8059G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004456.5(EZH2):​c.-7-8059G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 152,170 control chromosomes in the GnomAD database, including 44,310 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 0.75 (44310 hom., cov: 32)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 3 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004456.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.-7-8059G>A		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.-7-8059G>A		intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.-7-8059G>A		intron	N/A	NP_001190177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.-7-8059G>A		intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.-7-8059G>A		intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.-7-8059G>A		intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114610 AN: 152052 Hom.: 44251 Cov.: 32

Gnomad AFR AF: 0.937

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.669

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.736

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.754 AC: 114730 AN: 152170 Hom.: 44310 Cov.: 32 AF XY: 0.750 AC XY: 55772 AN XY: 74372

African (AFR) AF: 0.937 AC: 38920 AN: 41546

American (AMR) AF: 0.751 AC: 11484 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2364 AN: 3472

East Asian (EAS) AF: 0.669 AC: 3467 AN: 5182

South Asian (SAS) AF: 0.661 AC: 3179 AN: 4812

European-Finnish (FIN) AF: 0.595 AC: 6288 AN: 10560

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

European-Non Finnish (NFE) AF: 0.685 AC: 46600 AN: 67990

Other (OTH) AF: 0.737 AC: 1555 AN: 2110

Alfa AF: 0.716 Hom.: 11305

Bravo AF: 0.775

Asia WGS AF: 0.684 AC: 2381 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.1
DANN	Benign	0.25
PhyloP100		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs10274701; hg19: chr7-148552456;