7-148827145-C-G

Variant names:

• chr7-148827145-C-G
• rs114692729
• NM_004456.5:c.728+19G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004456.5(EZH2):​c.728+19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,597,520 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (4 hom.)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.307
• 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-148827145-C-G is Benign according to our data. Variant chr7-148827145-C-G is described in ClinVar as Benign. ClinVar VariationId is 259401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00515 (784/152258) while in subpopulation AFR AF = 0.0174 (723/41552). AF 95% confidence interval is 0.0163. There are 7 homozygotes in GnomAd4. There are 361 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 784 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.728+19G>C		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.728+19G>C		intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.701+19G>C		intron	N/A	NP_001190177.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.728+19G>C		intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.728+19G>C		intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.611+19G>C		intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.00513 AC: 780 AN: 152140 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00151 AC: 371 AN: 245418 AF XY: 0.00107

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000802

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000622 AC: 899 AN: 1445262 Hom.: 4 Cov.: 27 AF XY: 0.000525 AC XY: 378 AN XY: 719382

African (AFR) AF: 0.0183 AC: 598 AN: 32722

American (AMR) AF: 0.00101 AC: 44 AN: 43382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.0000356 AC: 3 AN: 84170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53256

Middle Eastern (MID) AF: 0.000700 AC: 4 AN: 5716

European-Non Finnish (NFE) AF: 0.000169 AC: 186 AN: 1100838

Other (OTH) AF: 0.00107 AC: 64 AN: 59764

GnomAD4 genome AF: 0.00515 AC: 784 AN: 152258 Hom.: 7 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74454

African (AFR) AF: 0.0174 AC: 723 AN: 41552

American (AMR) AF: 0.00301 AC: 46 AN: 15304

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

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00244 Hom.: 0

Bravo AF: 0.00593

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		-0.31
Mutation Taster		=100/0	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: rs114692729; hg19: chr7-148524237;