rs3757441

Variant names:

• chr7-148827660-C-T
• rs3757441
• NM_004456.5:c.626-394G>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.626-394G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 152,170 control chromosomes in the GnomAD database, including 48,638 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 0.80 (48638 hom., cov: 32)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.718
• Publications: 27 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.626-394G>A		intron_variant	Intron 6 of 19	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.626-394G>A		intron_variant	Intron 6 of 19	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120983 AN: 152052 Hom.: 48589 Cov.: 32

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.811

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.783

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

GnomAD4 genome AF: 0.796 AC: 121091 AN: 152170 Hom.: 48638 Cov.: 32 AF XY: 0.794 AC XY: 59035 AN XY: 74378

African (AFR) AF: 0.904 AC: 37566 AN: 41548

American (AMR) AF: 0.811 AC: 12415 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2560 AN: 3472

East Asian (EAS) AF: 0.756 AC: 3913 AN: 5176

South Asian (SAS) AF: 0.792 AC: 3813 AN: 4814

European-Finnish (FIN) AF: 0.660 AC: 6967 AN: 10552

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51265 AN: 67996

Other (OTH) AF: 0.786 AC: 1657 AN: 2108

Alfa AF: 0.771 Hom.: 74228

Bravo AF: 0.811

Asia WGS AF: 0.779 AC: 2709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.12
DANN	Benign	0.69
PhyloP100		-0.72
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: rs3757441; hg19: chr7-148524752;