17-42719183-T-G

Position:

• chr17-42719183-T-G

Variant summary

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

The ENST00000428826.7(EZH1):​c.689A>C​(p.Gln230Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EZH1 ENST00000428826.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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=0.20401895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH1	NM_001991.5	c.689A>C	p.Gln230Pro	missense_variant	8/21	ENST00000428826.7	NP_001982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH1	ENST00000428826.7	c.689A>C	p.Gln230Pro	missense_variant	8/21	1	NM_001991.5	ENSP00000404658	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.689A>C (p.Q230P) alteration is located in exon 8 (coding exon 6) of the EZH1 gene. This alteration results from a A to C substitution at nucleotide position 689, causing the glutamine (Q) at amino acid position 230 to be replaced by a proline (P). 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	0.084
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.060	T;T;T;.;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	.;T;T;T;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.20	N;.;N;.;.;.
MutationTaster	Benign	0.62	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.2	N;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.55	T;.;.;.;.;.
Sift4G	Benign	0.40	T;T;T;T;T;.
Polyphen		0.0	B;.;B;B;.;.
Vest4		0.37
MutPred		0.30		Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;.;.;
MVP		0.78
MPC		1.5
ClinPred		0.39	T
GERP RS		4.9
Varity_R		0.056
gMVP		0.68

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: rs1482782029; hg19: chr17-40871201;