chr7-148811729-T-C

Variant names:

• chr7-148811729-T-C
• rs199654408
• NM_004456.5:c.1852-9A>G

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.1852-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,608,126 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: EZH2 NM_004456.5 intron
• Scores: Splicing: ADA: 0.00004872
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.29
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-148811729-T-C is Benign according to our data. Variant chr7-148811729-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359278.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 = 0.00179 (272/152066) while in subpopulation NFE AF = 0.00343 (233/67996). AF 95% confidence interval is 0.00307. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 272 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.1852-9A>G		intron	N/A	NP_004447.2
	EZH2	NM_001203247.2		c.1837-9A>G		intron	N/A	NP_001190176.1	Q15910-1
	EZH2	NM_001203248.2		c.1810-9A>G		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.1852-9A>G		intron	N/A	ENSP00000320147.2	Q15910-2
	EZH2	ENST00000460911.5	TSL:1	c.1837-9A>G		intron	N/A	ENSP00000419711.1	Q15910-1
	EZH2	ENST00000350995.6	TSL:1	c.1720-9A>G		intron	N/A	ENSP00000223193.2	Q15910-3

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00169 AC: 417 AN: 246568 AF XY: 0.00173

Gnomad AFR exome AF: 0.000935

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00326 AC: 4743 AN: 1456060 Hom.: 12 Cov.: 29 AF XY: 0.00316 AC XY: 2290 AN XY: 724756

African (AFR) AF: 0.000628 AC: 21 AN: 33432

American (AMR) AF: 0.000380 AC: 17 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86194

European-Finnish (FIN) AF: 0.000262 AC: 13 AN: 49658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00409 AC: 4544 AN: 1110228

Other (OTH) AF: 0.00227 AC: 137 AN: 60300

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152066 Hom.: 0 Cov.: 33 AF XY: 0.00159 AC XY: 118 AN XY: 74270

African (AFR) AF: 0.000701 AC: 29 AN: 41394

American (AMR) AF: 0.000458 AC: 7 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00343 AC: 233 AN: 67996

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.00177

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.85
CADD	Benign	0.0050
DANN	Benign	0.59
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.062
Splicevardb		1.0
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: rs199654408; hg19: chr7-148508821;