7-148846601-TAAA-TAA

Variant names:

• chr7-148846601-TA-T
• rs3214332
• NM_004456.5:c.118-4delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000320356.7(EZH2):​c.118-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43236 hom., cov: 0)
  • Exomes 𝑓: 0.68 (272215 hom.)
• Consequence: EZH2 ENST00000320356.7 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.476
• 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 -16 ACMG points.

• BP6: Variant 7-148846601-TA-T is Benign according to our data. Variant chr7-148846601-TA-T is described in ClinVar as Benign. ClinVar VariationId is 210966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000320356.7. 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.118-4delT		splice_region intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.118-4delT		splice_region intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.118-4delT		splice_region 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.118-4delT		splice_region intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.118-4delT		splice_region intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.118-4delT		splice_region intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.751 AC: 112887 AN: 150286 Hom.: 43186 Cov.: 0

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.705

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.732

GnomAD2 exomes AF: 0.701 AC: 140067 AN: 199860 AF XY: 0.694

Gnomad AFR exome AF: 0.905

Gnomad AMR exome AF: 0.718

Gnomad ASJ exome AF: 0.693

Gnomad EAS exome AF: 0.673

Gnomad FIN exome AF: 0.629

Gnomad NFE exome AF: 0.692

Gnomad OTH exome AF: 0.692

GnomAD4 exome AF: 0.676 AC: 874854 AN: 1294816 Hom.: 272215 Cov.: 0 AF XY: 0.676 AC XY: 435388 AN XY: 644354

African (AFR) AF: 0.892 AC: 25278 AN: 28340

American (AMR) AF: 0.708 AC: 26916 AN: 37996

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 15583 AN: 22950

East Asian (EAS) AF: 0.659 AC: 23382 AN: 35460

South Asian (SAS) AF: 0.663 AC: 49530 AN: 74724

European-Finnish (FIN) AF: 0.620 AC: 29357 AN: 47370

Middle Eastern (MID) AF: 0.735 AC: 3889 AN: 5288

European-Non Finnish (NFE) AF: 0.672 AC: 664484 AN: 989526

Other (OTH) AF: 0.685 AC: 36435 AN: 53162

GnomAD4 genome AF: 0.751 AC: 112998 AN: 150404 Hom.: 43236 Cov.: 0 AF XY: 0.748 AC XY: 54870 AN XY: 73344

African (AFR) AF: 0.924 AC: 37976 AN: 41110

American (AMR) AF: 0.749 AC: 11325 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2357 AN: 3460

East Asian (EAS) AF: 0.670 AC: 3429 AN: 5118

South Asian (SAS) AF: 0.662 AC: 3144 AN: 4750

European-Finnish (FIN) AF: 0.599 AC: 6021 AN: 10048

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

European-Non Finnish (NFE) AF: 0.686 AC: 46344 AN: 67508

Other (OTH) AF: 0.733 AC: 1534 AN: 2094

Alfa AF: 0.626 Hom.: 3219

Bravo AF: 0.768

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Weaver syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3214332; hg19: chr7-148543693; COSMIC: COSV57447962;