7-148821919-C-T

Variant names:

• chr7-148821919-C-T
• rs6464926
• NM_004456.5:c.908-2232G>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.908-2232G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 151,898 control chromosomes in the GnomAD database, including 13,590 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 0.41 (13590 hom., cov: 32)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.751
• Publications: 9 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=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.908-2232G>A		intron_variant	Intron 8 of 19	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.908-2232G>A		intron_variant	Intron 8 of 19	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.415 AC: 62980 AN: 151784 Hom.: 13583 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.412

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

GnomAD4 genome AF: 0.415 AC: 63019 AN: 151898 Hom.: 13590 Cov.: 32 AF XY: 0.414 AC XY: 30694 AN XY: 74228

African (AFR) AF: 0.296 AC: 12231 AN: 41390

American (AMR) AF: 0.433 AC: 6615 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1457 AN: 3466

East Asian (EAS) AF: 0.408 AC: 2112 AN: 5174

South Asian (SAS) AF: 0.425 AC: 2041 AN: 4806

European-Finnish (FIN) AF: 0.432 AC: 4553 AN: 10542

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.479 AC: 32575 AN: 67944

Other (OTH) AF: 0.413 AC: 873 AN: 2116

Alfa AF: 0.435 Hom.: 2589

Bravo AF: 0.409

Asia WGS AF: 0.427 AC: 1483 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.41
DANN	Benign	0.41
PhyloP100		-0.75
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: rs6464926; hg19: chr7-148519011;