17-42719127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 12/21 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

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.49
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19102535).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EZH1NM_001991.5 linkc.745G>A p.Val249Ile missense_variant Exon 8 of 21 ENST00000428826.7 NP_001982.2 Q92800-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EZH1ENST00000428826.7 linkc.745G>A p.Val249Ile missense_variant Exon 8 of 21 1 NM_001991.5 ENSP00000404658.1 Q92800-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 04, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.745G>A (p.V249I) alteration is located in exon 8 (coding exon 6) of the EZH1 gene. This alteration results from a G to A substitution at nucleotide position 745, causing the valine (V) at amino acid position 249 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
T;T;T;.;.;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.071
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.89
.;D;D;D;D;D
M_CAP
Benign
0.076
D
MetaRNN
Benign
0.19
T;T;T;T;T;T
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Benign
0.90
L;.;L;.;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.60
N;.;.;.;.;.
REVEL
Benign
0.25
Sift
Benign
0.032
D;.;.;.;.;.
Sift4G
Benign
0.14
T;T;T;T;T;.
Polyphen
0.0090
B;.;B;B;.;.
Vest4
0.15
MutPred
0.23
Loss of catalytic residue at V249 (P = 0.0049);.;Loss of catalytic residue at V249 (P = 0.0049);.;.;.;
MVP
0.78
MPC
1.0
ClinPred
0.34
T
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1419961479; hg19: chr17-40871145; API