rs41277437

Variant names:

• chr7-148814079-C-T
• rs41277437
• NM_004456.5:c.1731G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-148814079-C-T
• chr7-148814079-C-A
• chr7-148814079-C-G

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.1731G>A​(p.Pro577Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,614,132 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 32)
  • Exomes 𝑓: 0.015 (210 hom.)
• Consequence: EZH2 NM_004456.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.07
• Publications: 10 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=-0.62).
• BP6: Variant 7-148814079-C-T is Benign according to our data. Variant chr7-148814079-C-T is described in ClinVar as Benign. ClinVar VariationId is 158577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1605/152262) while in subpopulation NFE AF = 0.0169 (1147/68032). AF 95% confidence interval is 0.016. There are 10 homozygotes in GnomAd4. There are 779 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1605 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.1731G>A	p.Pro577Pro	synonymous	Exon 15 of 20	NP_004447.2
	EZH2	NM_001203247.2		c.1716G>A	p.Pro572Pro	synonymous	Exon 15 of 20	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.1689G>A	p.Pro563Pro	synonymous	Exon 15 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.1731G>A	p.Pro577Pro	synonymous	Exon 15 of 20	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.1716G>A	p.Pro572Pro	synonymous	Exon 15 of 20	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.1599G>A	p.Pro533Pro	synonymous	Exon 14 of 19	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1605 AN: 152144 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0104 AC: 2616 AN: 251346 AF XY: 0.00973

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0153 AC: 22436 AN: 1461870 Hom.: 210 Cov.: 31 AF XY: 0.0146 AC XY: 10637 AN XY: 727240

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00333 AC: 149 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00232 AC: 200 AN: 86258

European-Finnish (FIN) AF: 0.0262 AC: 1400 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0178 AC: 19773 AN: 1111990

Other (OTH) AF: 0.0126 AC: 761 AN: 60396

GnomAD4 genome AF: 0.0105 AC: 1605 AN: 152262 Hom.: 10 Cov.: 32 AF XY: 0.0105 AC XY: 779 AN XY: 74442

African (AFR) AF: 0.00308 AC: 128 AN: 41530

American (AMR) AF: 0.00360 AC: 55 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0169 AC: 1147 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0131 Hom.: 10

Bravo AF: 0.00897

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0129

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.2
DANN	Benign	0.58
PhyloP100		-4.1
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: rs41277437; hg19: chr7-148511171; COSMIC: COSV57446654;