rs112932272

Positions:

• chr7-148828887-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004456.5(EZH2):​c.485-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,599,316 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: EZH2 NM_004456.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005139
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.217

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 7-148828887-C-T is Benign according to our data. Variant chr7-148828887-C-T is described in ClinVar as [Benign]. Clinvar id is 198172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148828887-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00935 (1421/152012) while in subpopulation AFR AF= 0.0325 (1346/41466). AF 95% confidence interval is 0.031. There are 16 homozygotes in gnomad4. There are 654 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1421 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH2	NM_004456.5	c.485-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.485-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004456.5	ENSP00000320147	P4

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1417 AN: 151892 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00672

GnomAD3 exomes AF: 0.00288 AC: 639 AN: 222022 Hom.: 6 AF XY: 0.00209 AC XY: 250 AN XY: 119768

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000621

Gnomad SAS exome AF: 0.000637

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000833

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.00115 AC: 1661 AN: 1447304 Hom.: 30 Cov.: 31 AF XY: 0.00104 AC XY: 746 AN XY: 718828

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000485

Gnomad4 SAS exome AF: 0.000735

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00935 AC: 1421 AN: 152012 Hom.: 16 Cov.: 32 AF XY: 0.00880 AC XY: 654 AN XY: 74284

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.00665

Alfa AF: 0.00458 Hom.: 2

Bravo AF: 0.0107

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Weaver syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.2
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs112932272; hg19: chr7-148525979; COSMIC: COSV104539089;