17-42718486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001991.5(EZH1):​c.899G>A​(p.Arg300Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EZH1
NM_001991.5 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EZH1NM_001991.5 linkc.899G>A p.Arg300Gln missense_variant Exon 9 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.899G>A p.Arg300Gln missense_variant Exon 9 of 21 1 NM_001991.5 ENSP00000404658.1 Q92800-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461784
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
May 10, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
D;T;D;.;.;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D;D
MetaSVM
Uncertain
0.29
D
MutationAssessor
Uncertain
2.4
M;.;M;.;.;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-3.7
D;.;.;.;.;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.019
D;.;.;.;.;.
Sift4G
Uncertain
0.011
D;D;D;D;D;.
Polyphen
0.96
D;.;D;D;.;.
Vest4
0.82
MutPred
0.61
Gain of ubiquitination at K304 (P = 0.0442);.;Gain of ubiquitination at K304 (P = 0.0442);.;.;.;
MVP
0.87
MPC
1.7
ClinPred
0.98
D
GERP RS
4.7
Varity_R
0.59
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-40870504; API