Genetic Variant JADE3:p.Val225Ile (chrX-47028089-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014735.5(JADE3):c.673G>A(p.Val225Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,199,784 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000010 ( 0 hom. 6 hem. )

Consequence

JADE3
NM_014735.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.02

Variant links:

Genes affected

JADE3 (HGNC:22982): (jade family PHD finger 3) This gene encodes a member of a family of large proteins containing PHD (plant homeo domain)-type zinc fingers. The encoded protein may be associated in a nuclear complex that functions in histone H4 acetylation. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Aug 2013]

JADE3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05271378).

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JADE3	NM_014735.5 link	c.673G>A	p.Val225Ile	missense_variant	Exon 6 of 11	ENST00000614628.5	NP_055550.1	Q92613A0A024R1A2
JADE3	NM_001077445.3 link	c.673G>A	p.Val225Ile	missense_variant	Exon 6 of 11		NP_001070913.1	Q92613A0A024R1A2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JADE3	ENST00000614628.5 link	c.673G>A	p.Val225Ile	missense_variant	Exon 6 of 11	1	NM_014735.5	ENSP00000481850.1	Q92613
JADE3	ENST00000611250.4 link	c.673G>A	p.Val225Ile	missense_variant	Exon 6 of 11	2		ENSP00000479377.1	Q92613
JADE3	ENST00000424392.5 link	c.*113G>A		downstream_gene_variant		3		ENSP00000391009.1	F2Z3N8

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111548

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33718

show subpopulations

Gnomad AFR

AF:

0.0000978

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

181844

Hom.:

AF XY:

0.00

AC XY:

AN XY:

66492

show subpopulations

Gnomad AFR exome

AF:

0.000153

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1088180

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

353906

show subpopulations

Gnomad4 AFR exome

AF:

0.000267

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111604

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33784

show subpopulations

Gnomad4 AFR

AF:

0.0000975

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 16, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.6

DANN

Benign

0.64

DEOGEN2

Benign

0.13

T;T

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.80

T;.

M_CAP

Benign

0.029

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.10

N;N

PrimateAI

Benign

0.41

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.14

MutPred

0.62

Loss of catalytic residue at V225 (P = 0.0316);Loss of catalytic residue at V225 (P = 0.0316);

MVP

0.068

ClinPred

0.016

GERP RS

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.65

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

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