chr7-148832759-G-GA

Variant names:

• chr7-148832759-G-GA
• rs557474218
• NM_004456.5:c.247-10dupT

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.247-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,555,412 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (19 hom.)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 7-148832759-G-GA is Benign according to our data. Variant chr7-148832759-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00295 (448/151972) while in subpopulation NFE AF = 0.0048 (326/67924). AF 95% confidence interval is 0.00437. There are 0 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 448 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.247-10dupT		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.247-10dupT		intron	N/A	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.220-10dupT		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.247-10_247-9insT		intron	N/A	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.247-10_247-9insT		intron	N/A	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.247-2912_247-2911insT		intron	N/A	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 151854 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00286 AC: 691 AN: 241264 AF XY: 0.00287

Gnomad AFR exome AF: 0.000564

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.000749

Gnomad EAS exome AF: 0.0000567

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00419 AC: 5887 AN: 1403440 Hom.: 19 Cov.: 22 AF XY: 0.00406 AC XY: 2843 AN XY: 700048

African (AFR) AF: 0.000662 AC: 21 AN: 31726

American (AMR) AF: 0.00284 AC: 117 AN: 41186

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 23 AN: 25060

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39258

South Asian (SAS) AF: 0.000144 AC: 12 AN: 83174

European-Finnish (FIN) AF: 0.000796 AC: 42 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00512 AC: 5459 AN: 1066702

Other (OTH) AF: 0.00366 AC: 212 AN: 57974

GnomAD4 genome AF: 0.00295 AC: 448 AN: 151972 Hom.: 0 Cov.: 32 AF XY: 0.00269 AC XY: 200 AN XY: 74286

African (AFR) AF: 0.000868 AC: 36 AN: 41480

American (AMR) AF: 0.00419 AC: 64 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00114 AC: 12 AN: 10524

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

European-Non Finnish (NFE) AF: 0.00480 AC: 326 AN: 67924

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00360 Hom.: 0

Bravo AF: 0.00328

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Weaver syndrome (2)
-	-	1	EZH2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=99/1	polymorphism

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: rs557474218; hg19: chr7-148529851;