rs41277434

Variant names:

• chr7-148809304-A-C
• rs41277434
• NM_004456.5:c.2110+6T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-148809304-A-C
• chr7-148809304-A-G

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.2110+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,600,172 control chromosomes in the GnomAD database, including 3,257 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 0.050 (290 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2967 hom.)
• Consequence: EZH2 NM_004456.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003168
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.791
• Publications: 27 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=-0.81).
• BP6: Variant 7-148809304-A-C is Benign according to our data. Variant chr7-148809304-A-C is described in ClinVar as Benign. ClinVar VariationId is 137273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH2	NM_004456.5	c.2110+6T>G		splice_region_variant, intron_variant	Intron 18 of 19	ENST00000320356.7	NP_004447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH2	ENST00000320356.7	c.2110+6T>G		splice_region_variant, intron_variant	Intron 18 of 19	1	NM_004456.5	ENSP00000320147.2

Frequencies

GnomAD3 genomes AF: 0.0503 AC: 7661 AN: 152232 Hom.: 286 Cov.: 33

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0547

Gnomad OTH AF: 0.0545

GnomAD2 exomes AF: 0.0682 AC: 17153 AN: 251348 AF XY: 0.0651

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.0587

Gnomad EAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0690

Gnomad NFE exome AF: 0.0526

Gnomad OTH exome AF: 0.0692

GnomAD4 exome AF: 0.0576 AC: 83363 AN: 1447822 Hom.: 2967 Cov.: 31 AF XY: 0.0571 AC XY: 40944 AN XY: 716946

African (AFR) AF: 0.0174 AC: 580 AN: 33298

American (AMR) AF: 0.173 AC: 7704 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.0599 AC: 1559 AN: 26040

East Asian (EAS) AF: 0.0526 AC: 2066 AN: 39284

South Asian (SAS) AF: 0.0459 AC: 3948 AN: 85962

European-Finnish (FIN) AF: 0.0665 AC: 3542 AN: 53290

Middle Eastern (MID) AF: 0.0826 AC: 474 AN: 5738

European-Non Finnish (NFE) AF: 0.0546 AC: 60068 AN: 1099912

Other (OTH) AF: 0.0573 AC: 3422 AN: 59756

GnomAD4 genome AF: 0.0503 AC: 7663 AN: 152350 Hom.: 290 Cov.: 33 AF XY: 0.0511 AC XY: 3805 AN XY: 74490

African (AFR) AF: 0.0191 AC: 794 AN: 41582

American (AMR) AF: 0.109 AC: 1666 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3470

East Asian (EAS) AF: 0.0370 AC: 192 AN: 5192

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4828

European-Finnish (FIN) AF: 0.0662 AC: 703 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0547 AC: 3721 AN: 68036

Other (OTH) AF: 0.0539 AC: 114 AN: 2114

Alfa AF: 0.0556 Hom.: 222

Bravo AF: 0.0552

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.0579

EpiControl AF: 0.0561

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Mar 07, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Weaver syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	18
DANN	Benign	0.67
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.12		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: rs41277434; hg19: chr7-148506396; COSMIC: COSV57446454; COSMIC: COSV57446454;