Genetic Variant EZHIP:p.Ala289Thr (chrX-51407881-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_203407.3(EZHIP):c.865G>A(p.Ala289Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 555,525 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.00014 ( 0 hom. 17 hem. )

Consequence

EZHIP
NM_203407.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.26

Variant links:

Genes affected

EZHIP (HGNC:33738): (EZH inhibitory protein) Involved in negative regulation of histone H3-K27 methylation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

EZHIP links:

ENSG00000226530 (HGNC:):

ENSG00000226530 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04451242).

BP6

Variant X-51407881-G-A is Benign according to our data. Variant chrX-51407881-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660567.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZHIP	NM_203407.3 link	c.865G>A	p.Ala289Thr	missense_variant	Exon 1 of 1	ENST00000342995.4	NP_981952.1	Q86X51A0A515VFR0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZHIP	ENST00000342995.4 link	c.865G>A	p.Ala289Thr	missense_variant	Exon 1 of 1	6	NM_203407.3	ENSP00000342680.2		Q86X51
ENSG00000226530	ENST00000455931.2 link	n.757+11200G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

112234

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34410

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000370

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00427

Gnomad NFE

AF:

0.000208

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000114

AC:

AN:

149614

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

50118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000767

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000233

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000140

AC:

AN:

443244

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

162442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000195

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000202

Gnomad4 OTH exome

AF:

0.0000819

GnomAD4 genome

AF:

0.000116

AC:

AN:

112281

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34467

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000371

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000208

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000121

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EZHIP: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.93

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.034

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.46

M_CAP

Benign

0.012

MetaRNN

Benign

0.045

MetaSVM

Benign

-1.0

PROVEAN

Benign

-2.2

REVEL

Benign

0.033

Sift

Benign

0.23

Sift4G

Uncertain

0.040

Polyphen

0.22

Vest4

0.021

MVP

0.36

MPC

0.11

ClinPred

0.049

GERP RS

-2.0

Varity_R

0.11

gMVP

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over