7-148811729-T-C

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.1852-9A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004872
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.29

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=-0.85).
• BP6: Variant 7-148811729-T-C is Benign according to our data. Variant chr7-148811729-T-C is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZH2	NM_004456.5	c.1852-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000320356.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZH2	ENST00000320356.7	c.1852-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004456.5	P4

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

GnomAD3 exomes AF: 0.00169 AC: 417 AN: 246568 Hom.: 1 AF XY: 0.00173 AC XY: 232 AN XY: 133916

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 SAS exome AF: 0.0000656

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

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00409

Gnomad4 OTH exome AF: 0.00227

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

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00343

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.00177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 25, 2018

- -

Weaver syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.0050
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.062
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: rs199654408; hg19: chr7-148508821; COSMIC: COSV104538072;