17-42709886-C-A

Variant names:

• chr17-42709886-C-A
• NM_001991.5:c.1453G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001991.5(EZH1):​c.1453G>T​(p.Glu485*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EZH1 NM_001991.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.03
• Publications: 1 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42709886-C-A is Pathogenic according to our data. Variant chr17-42709886-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2570598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1453G>T	p.Glu485*	stop_gained	Exon 13 of 21	NP_001982.2
	EZH1	NM_001321079.2		c.1471G>T	p.Glu491*	stop_gained	Exon 12 of 20	NP_001308008.1	Q92800-2
	EZH1	NM_001321081.2		c.1426G>T	p.Glu476*	stop_gained	Exon 13 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.1453G>T	p.Glu485*	stop_gained	Exon 13 of 21	ENSP00000404658.1	Q92800-1
	EZH1	ENST00000415827.6	TSL:1	c.1426G>T	p.Glu476*	stop_gained	Exon 13 of 21	ENSP00000407869.2	A0A0A0MSY9
	EZH1	ENST00000585550.5	TSL:1	n.685G>T		non_coding_transcript_exon	Exon 5 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	EZH1-neurodevelopmental syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.0
Vest4		0.96
GERP RS		5.3
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

hg19: chr17-40861904;