7-148846601-T-TA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004456.5(EZH2):​c.118-4dupT 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: EZH2 NM_004456.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-T-TA is Benign according to our data. Variant chr7-148846601-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2193760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000106 (16/150502) while in subpopulation SAS AF = 0.00126 (6/4754). AF 95% confidence interval is 0.000549. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.118-4dupT		splice_region intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.118-4dupT		splice_region intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.118-4dupT		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.118-4_118-3insT		splice_region intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.118-4_118-3insT		splice_region intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.118-4_118-3insT		splice_region intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 150384 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000891 AC: 178 AN: 199860 AF XY: 0.000938

Gnomad AFR exome AF: 0.000224

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000630

Gnomad EAS exome AF: 0.000478

Gnomad FIN exome AF: 0.000722

Gnomad NFE exome AF: 0.000876

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000721 AC: 943 AN: 1307800 Hom.: 0 Cov.: 0 AF XY: 0.000753 AC XY: 490 AN XY: 651090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000106 AC: 3 AN: 28360

American (AMR) AF: 0.00102 AC: 39 AN: 38296

Ashkenazi Jewish (ASJ) AF: 0.000559 AC: 13 AN: 23274

East Asian (EAS) AF: 0.000585 AC: 21 AN: 35906

South Asian (SAS) AF: 0.00144 AC: 109 AN: 75920

European-Finnish (FIN) AF: 0.000996 AC: 48 AN: 48196

Middle Eastern (MID) AF: 0.000753 AC: 4 AN: 5312

European-Non Finnish (NFE) AF: 0.000663 AC: 662 AN: 998792

Other (OTH) AF: 0.000819 AC: 44 AN: 53744

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000106 AC: 16 AN: 150502 Hom.: 0 Cov.: 0 AF XY: 0.000109 AC XY: 8 AN XY: 73408

African (AFR) AF: 0.0000730 AC: 3 AN: 41114

American (AMR) AF: 0.00 AC: 0 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000104 AC: 7 AN: 67546

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00194 Hom.: 3219

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Weaver syndrome (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;