17-42713293-T-C

Variant names:

• chr17-42713293-T-C
• rs2053526016
• NM_001991.5:c.1120A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001991.5(EZH1):​c.1120A>G​(p.Asn374Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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]

ACMG classification

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=0.14177111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH1	NM_001991.5	c.1120A>G	p.Asn374Asp	missense_variant	Exon 11 of 21	ENST00000428826.7	NP_001982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH1	ENST00000428826.7	c.1120A>G	p.Asn374Asp	missense_variant	Exon 11 of 21	1	NM_001991.5	ENSP00000404658.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 28, 2024

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 does not alter 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	Benign	0.099
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	.;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.8	L;.;L;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.34	N;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.44	T;.;.;.;.
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.21	B;.;B;B;B
Vest4		0.28
MutPred		0.10		Loss of MoRF binding (P = 0.0618);.;Loss of MoRF binding (P = 0.0618);.;.;
MVP		0.70
MPC		2.6
ClinPred		0.88	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2053526016; hg19: chr17-40865311;