chr7-148846601-TAA-T

Variant names:

• chr7-148846601-TAA-T
• rs3214332
• NM_004456.5:c.118-5_118-4delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_004456.5(EZH2):​c.118-5_118-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,444,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: EZH2 NM_004456.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.231
• 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP6: Variant 7-148846601-TAA-T is Benign according to our data. Variant chr7-148846601-TAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.118-5_118-4delTT		splice_region intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.118-5_118-4delTT		splice_region intron	N/A	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.118-5_118-4delTT		splice_region intron	N/A	NP_001190177.1	Q15910-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.118-5_118-4delTT		splice_region intron	N/A	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.118-5_118-4delTT		splice_region intron	N/A	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.118-5_118-4delTT		splice_region intron	N/A	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.0000466 AC: 7 AN: 150354 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000993

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00290 AC: 579 AN: 199860 AF XY: 0.00295

Gnomad AFR exome AF: 0.00366

Gnomad AMR exome AF: 0.00456

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00259

Gnomad FIN exome AF: 0.000889

Gnomad NFE exome AF: 0.00263

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00134 AC: 1729 AN: 1293712 Hom.: 0 AF XY: 0.00134 AC XY: 864 AN XY: 643960

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

African (AFR) AF: 0.00328 AC: 90 AN: 27436

American (AMR) AF: 0.00373 AC: 140 AN: 37566

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 30 AN: 22942

East Asian (EAS) AF: 0.000956 AC: 34 AN: 35576

South Asian (SAS) AF: 0.00231 AC: 173 AN: 74884

European-Finnish (FIN) AF: 0.000816 AC: 39 AN: 47818

Middle Eastern (MID) AF: 0.00114 AC: 6 AN: 5262

European-Non Finnish (NFE) AF: 0.00116 AC: 1143 AN: 989106

Other (OTH) AF: 0.00139 AC: 74 AN: 53122

⚠️ 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: 0.0000532 AC: 8 AN: 150472 Hom.: 0 Cov.: 0 AF XY: 0.0000273 AC XY: 2 AN XY: 73390

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

African (AFR) AF: 0.0000486 AC: 2 AN: 41110

American (AMR) AF: 0.00 AC: 0 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4754

European-Finnish (FIN) AF: 0.0000993 AC: 1 AN: 10074

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

European-Non Finnish (NFE) AF: 0.0000740 AC: 5 AN: 67530

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000126290), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0153 Hom.: 3219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Weaver syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=98/2	polymorphism

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;