Genetic Variant EZH1:p.Val249Ile (chr17-42719127-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001991.5(EZH1):c.745G>A(p.Val249Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EZH1
NM_001991.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49

Publications

0 publications found

Variant links:

Genes affected

EZH1 (HGNC:3526): (enhancer of zeste 1 polycomb repressive complex 2 subunit) EZH1 is a component of a noncanonical Polycomb repressive complex-2 (PRC2) that mediates methylation of histone H3 (see MIM 602812) lys27 (H3K27) and functions in the maintenance of embryonic stem cell pluripotency and plasticity (Shen et al., 2008 [PubMed 19026780]).[supplied by OMIM, Mar 2009]

EZH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.1984 (above the threshold of 3.09). Trascript score misZ: 5.5841 (above the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.19102535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001991.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EZH1	NM_001991.5	MANE Select	c.745G>A	p.Val249Ile	missense	Exon 8 of 21	NP_001982.2
EZH1	NM_001321079.2		c.763G>A	p.Val255Ile	missense	Exon 7 of 20	NP_001308008.1	Q92800-2
EZH1	NM_001321081.2		c.718G>A	p.Val240Ile	missense	Exon 8 of 21	NP_001308010.1	A0A0A0MSY9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EZH1	ENST00000428826.7	TSL:1 MANE Select	c.745G>A	p.Val249Ile	missense	Exon 8 of 21	ENSP00000404658.1	Q92800-1
EZH1	ENST00000415827.6	TSL:1	c.718G>A	p.Val240Ile	missense	Exon 8 of 21	ENSP00000407869.2	A0A0A0MSY9
EZH1	ENST00000586382.5	TSL:1	c.598G>A	p.Val200Ile	missense	Exon 7 of 10	ENSP00000464753.1	K7EIH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.071

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.076

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.90

PhyloP100

2.5

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.60

REVEL

Benign

0.25

Sift

Benign

0.032

Sift4G

Benign

0.14

Polyphen

0.0090

Vest4

0.15

MutPred

0.23

Loss of catalytic residue at V249 (P = 0.0049)

MVP

0.78

MPC

1.0

ClinPred

0.34

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.040

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over