17-42712473-C-T

Variant names:

• chr17-42712473-C-T
• rs1597832055
• NM_001991.5:c.1217G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001991.5(EZH1):​c.1217G>A​(p.Arg406His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EZH1 NM_001991.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.1984 (above the threshold of 3.09). Trascript score misZ: 5.5841 (above the threshold of 3.09).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001991.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH1	NM_001991.5	MANE Select	c.1217G>A	p.Arg406His	missense	Exon 12 of 21	NP_001982.2
	EZH1	NM_001321079.2		c.1235G>A	p.Arg412His	missense	Exon 11 of 20	NP_001308008.1	Q92800-2
	EZH1	NM_001321081.2		c.1190G>A	p.Arg397His	missense	Exon 12 of 21	NP_001308010.1	A0A0A0MSY9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZH1	ENST00000428826.7	TSL:1 MANE Select	c.1217G>A	p.Arg406His	missense	Exon 12 of 21	ENSP00000404658.1	Q92800-1
	EZH1	ENST00000415827.6	TSL:1	c.1190G>A	p.Arg397His	missense	Exon 12 of 21	ENSP00000407869.2	A0A0A0MSY9
	EZH1	ENST00000585550.5	TSL:1	n.449G>A		non_coding_transcript_exon	Exon 4 of 11

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.9	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.58
MutPred		0.20		Gain of glycosylation at T409 (P = 0.0841)
MVP		0.87
MPC		2.2
ClinPred		0.89	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1597832055; hg19: chr17-40864491;