rs370302056

Variant names:

• chr7-148829718-T-C
• rs370302056
• NM_004456.5:c.484+10A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004456.5(EZH2):​c.484+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,607,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.356
• 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-148829718-T-C is Benign according to our data. Variant chr7-148829718-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 528799.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000092 (14/152202) while in subpopulation NFE AF = 0.000162 (11/68026). AF 95% confidence interval is 0.0000905. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.484+10A>G		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.484+10A>G		intron	N/A	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.457+10A>G		intron	N/A	NP_001190177.1	Q15910-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.484+10A>G		intron	N/A	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.484+10A>G		intron	N/A	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.367+10A>G		intron	N/A	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000693 AC: 17 AN: 245164 AF XY: 0.0000831

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1454980 Hom.: 0 Cov.: 30 AF XY: 0.000131 AC XY: 95 AN XY: 723458

African (AFR) AF: 0.0000605 AC: 2 AN: 33082

American (AMR) AF: 0.0000462 AC: 2 AN: 43246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39428

South Asian (SAS) AF: 0.00 AC: 0 AN: 84098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000150 AC: 166 AN: 1110212

Other (OTH) AF: 0.000133 AC: 8 AN: 60154

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74372

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000992 Hom.: 0

Bravo AF: 0.0000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Weaver syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.57
PhyloP100		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs370302056; hg19: chr7-148526810;