7-148818100-A-G

Variant names:

• chr7-148818100-A-G
• rs77051363
• NM_004456.5:c.1017T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004456.5(EZH2):​c.1017T>C​(p.Phe339Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,594,402 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (36 hom.)
• Consequence: EZH2 NM_004456.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0940
• 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: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-148818100-A-G is Benign according to our data. Variant chr7-148818100-A-G is described in ClinVar as Benign. ClinVar VariationId is 158576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.094 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1883/152322) while in subpopulation AFR AF = 0.0428 (1780/41556). AF 95% confidence interval is 0.0412. There are 46 homozygotes in GnomAd4. There are 874 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1883 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.1017T>C	p.Phe339Phe	synonymous	Exon 10 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.1002T>C	p.Phe334Phe	synonymous	Exon 10 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.975T>C	p.Phe325Phe	synonymous	Exon 10 of 20	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.1017T>C	p.Phe339Phe	synonymous	Exon 10 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.1002T>C	p.Phe334Phe	synonymous	Exon 10 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.885T>C	p.Phe295Phe	synonymous	Exon 9 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1873 AN: 152204 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00337 AC: 776 AN: 230276 AF XY: 0.00228

Gnomad AFR exome AF: 0.0435

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000750

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.00117 AC: 1688 AN: 1442080 Hom.: 36 Cov.: 31 AF XY: 0.000991 AC XY: 709 AN XY: 715718

African (AFR) AF: 0.0415 AC: 1345 AN: 32402

American (AMR) AF: 0.00236 AC: 97 AN: 41076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.000108 AC: 9 AN: 82968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52974

Middle Eastern (MID) AF: 0.00253 AC: 14 AN: 5528

European-Non Finnish (NFE) AF: 0.0000326 AC: 36 AN: 1103088

Other (OTH) AF: 0.00315 AC: 187 AN: 59452

GnomAD4 genome AF: 0.0124 AC: 1883 AN: 152322 Hom.: 46 Cov.: 32 AF XY: 0.0117 AC XY: 874 AN XY: 74484

African (AFR) AF: 0.0428 AC: 1780 AN: 41556

American (AMR) AF: 0.00451 AC: 69 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68044

Other (OTH) AF: 0.0114 AC: 24 AN: 2112

Alfa AF: 0.00614 Hom.: 12

Bravo AF: 0.0138

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		0.094
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	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: rs77051363; hg19: chr7-148515192;