17-42718068-C-T

Variant names:

• chr17-42718068-C-T
• NM_001991.5:c.932-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001991.5(EZH1):​c.932-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EZH1 NM_001991.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.01
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-42718068-C-T is Pathogenic according to our data. Variant chr17-42718068-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2570599.Status of the report is criteria_provided_single_submitter, 1 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.932-1G>A		splice_acceptor intron	N/A	NP_001982.2
	EZH1	NM_001321079.2		c.950-1G>A		splice_acceptor intron	N/A	NP_001308008.1	Q92800-2
	EZH1	NM_001321081.2		c.905-1G>A		splice_acceptor intron	N/A	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.932-1G>A		splice_acceptor intron	N/A	ENSP00000404658.1	Q92800-1
	EZH1	ENST00000415827.6	TSL:1	c.905-1G>A		splice_acceptor intron	N/A	ENSP00000407869.2	A0A0A0MSY9
	EZH1	ENST00000586382.5	TSL:1	c.785-1G>A		splice_acceptor intron	N/A	ENSP00000464753.1	K7EIH5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	EZH1-neurodevelopmental syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.0
GERP RS		3.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 39
DS_AL_spliceai		0.80		Position offset: -1

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

Other links and lift over

hg19: chr17-40870086;