7-148808972-A-G

Variant names:

• chr7-148808972-A-G
• rs740949
• NM_004456.5:c.2195+99T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004456.5(EZH2):​c.2195+99T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 917,260 control chromosomes in the GnomAD database, including 227,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39791 hom., cov: 32)
  • Exomes 𝑓: 0.70 (187442 hom.)
• Consequence: EZH2 NM_004456.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0940
• Publications: 8 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=-0.94).
• BP6: Variant 7-148808972-A-G is Benign according to our data. Variant chr7-148808972-A-G is described in ClinVar as Benign. ClinVar VariationId is 680128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	NM_004456.5	MANE Select	c.2195+99T>C		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.2180+99T>C		intron	N/A	NP_001190176.1
	EZH2	NM_001203248.2		c.2153+99T>C		intron	N/A	NP_001190177.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH2	ENST00000320356.7	TSL:1 MANE Select	c.2195+99T>C		intron	N/A	ENSP00000320147.2
	EZH2	ENST00000460911.5	TSL:1	c.2180+99T>C		intron	N/A	ENSP00000419711.1
	EZH2	ENST00000350995.6	TSL:1	c.2063+99T>C		intron	N/A	ENSP00000223193.2

Frequencies

GnomAD3 genomes AF: 0.721 AC: 109594 AN: 152060 Hom.: 39767 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.722

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.704

GnomAD4 exome AF: 0.699 AC: 534566 AN: 765082 Hom.: 187442 AF XY: 0.696 AC XY: 278269 AN XY: 400048

African (AFR) AF: 0.791 AC: 14877 AN: 18814

American (AMR) AF: 0.739 AC: 22991 AN: 31108

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 12433 AN: 18040

East Asian (EAS) AF: 0.660 AC: 23522 AN: 35626

South Asian (SAS) AF: 0.630 AC: 37614 AN: 59660

European-Finnish (FIN) AF: 0.678 AC: 33167 AN: 48904

Middle Eastern (MID) AF: 0.680 AC: 2872 AN: 4226

European-Non Finnish (NFE) AF: 0.706 AC: 361542 AN: 511968

Other (OTH) AF: 0.695 AC: 25548 AN: 36736

GnomAD4 genome AF: 0.721 AC: 109673 AN: 152178 Hom.: 39791 Cov.: 32 AF XY: 0.718 AC XY: 53440 AN XY: 74394

African (AFR) AF: 0.786 AC: 32603 AN: 41506

American (AMR) AF: 0.742 AC: 11346 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2355 AN: 3470

East Asian (EAS) AF: 0.671 AC: 3482 AN: 5186

South Asian (SAS) AF: 0.626 AC: 3018 AN: 4820

European-Finnish (FIN) AF: 0.660 AC: 6990 AN: 10590

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47603 AN: 67992

Other (OTH) AF: 0.705 AC: 1490 AN: 2114

Alfa AF: 0.682 Hom.: 7185

Bravo AF: 0.732

Asia WGS AF: 0.669 AC: 2328 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		0.094
Mutation Taster		=100/0	polymorphism (auto)

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: rs740949; hg19: chr7-148506064; COSMIC: COSV100234625;