17-42719127-C-T

Variant names:

• chr17-42719127-C-T
• rs1419961479
• NM_001991.5:c.745G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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=0.19102535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZH1	NM_001991.5	c.745G>A	p.Val249Ile	missense_variant	Exon 8 of 21	ENST00000428826.7	NP_001982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZH1	ENST00000428826.7	c.745G>A	p.Val249Ile	missense_variant	Exon 8 of 21	1	NM_001991.5	ENSP00000404658.1

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

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

Other links and lift over

dbSNP: rs1419961479; hg19: chr17-40871145;