17-42713308-T-C

Position:

• chr17-42713308-T-C

Variant summary

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

The NM_001991.5(EZH1):​c.1105A>G​(p.Ser369Gly) 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. 14/21 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: 2.83

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=0.15759706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZH1	NM_001991.5	c.1105A>G	p.Ser369Gly	missense_variant	11/21	ENST00000428826.7	NP_001982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZH1	ENST00000428826.7	c.1105A>G	p.Ser369Gly	missense_variant	11/21	1	NM_001991.5	ENSP00000404658	P1

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.1105A>G (p.S369G) alteration is located in exon 11 (coding exon 9) of the EZH1 gene. This alteration results from a A to G substitution at nucleotide position 1105, causing the serine (S) at amino acid position 369 to be replaced by a glycine (G). 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	0.053
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	T;T;T;.;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	.;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.3	L;.;L;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.14	N;N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.36	T;T;.;.;.
Sift4G	Benign	0.42	T;T;T;T;T
Polyphen		0.0030	B;.;B;B;B
Vest4		0.11
MutPred		0.31		Loss of glycosylation at S369 (P = 0.0169);.;Loss of glycosylation at S369 (P = 0.0169);.;.;
MVP		0.75
MPC		1.1
ClinPred		0.58	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.50

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: rs2053526344; hg19: chr17-40865326;