rs12670401

Variant names:

• chr7-148865843-T-C
• rs12670401
• NM_004456.5:c.-8+18321A>G

Variant summary

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

The NM_004456.5(EZH2):​c.-8+18321A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 152,066 control chromosomes in the GnomAD database, including 13,463 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 (13463 hom., cov: 32)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214
• Publications: 6 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=-0.76).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.-8+18321A>G		intron_variant	Intron 1 of 19	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.-8+18321A>G		intron_variant	Intron 1 of 19	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62676 AN: 151948 Hom.: 13458 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.425

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.408

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

GnomAD4 genome AF: 0.412 AC: 62714 AN: 152066 Hom.: 13463 Cov.: 32 AF XY: 0.411 AC XY: 30529 AN XY: 74346

African (AFR) AF: 0.292 AC: 12139 AN: 41504

American (AMR) AF: 0.428 AC: 6535 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3472

East Asian (EAS) AF: 0.415 AC: 2144 AN: 5162

South Asian (SAS) AF: 0.417 AC: 2012 AN: 4824

European-Finnish (FIN) AF: 0.425 AC: 4488 AN: 10558

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.479 AC: 32536 AN: 67960

Other (OTH) AF: 0.408 AC: 863 AN: 2114

Alfa AF: 0.455 Hom.: 49441

Bravo AF: 0.408

Asia WGS AF: 0.426 AC: 1480 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.4
DANN	Benign	0.91
PhyloP100		0.21
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: rs12670401; hg19: chr7-148562935;