X-46985745-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014735.5(JADE3):c.79T>C(p.Tyr27His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,048 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
• Consequence: JADE3 NM_014735.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15097794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JADE3	NM_014735.5	c.79T>C	p.Tyr27His	missense_variant	3/11	ENST00000614628.5
JADE3	NM_001077445.3	c.79T>C	p.Tyr27His	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JADE3	ENST00000614628.5	c.79T>C	p.Tyr27His	missense_variant	3/11	1	NM_014735.5	P1
JADE3	ENST00000611250.4	c.79T>C	p.Tyr27His	missense_variant	3/11	2		P1
JADE3	ENST00000424392.5	c.79T>C	p.Tyr27His	missense_variant	3/6	3
JADE3	ENST00000455411.1	c.79T>C	p.Tyr27His	missense_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112048 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34204

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 26

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112048 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34204

Gnomad4 AFR AF: 0.00

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: 0.0000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.79T>C (p.Y27H) alteration is located in exon 3 (coding exon 2) of the JADE3 gene. This alteration results from a T to C substitution at nucleotide position 79, causing the tyrosine (Y) at amino acid position 27 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	17
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.54	T;T;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.50	N;.;.;N
REVEL	Benign	0.18
Sift	Benign	0.36	T;.;.;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.32, 0.36
MutPred		0.17		Loss of phosphorylation at Y27 (P = 0.031);Loss of phosphorylation at Y27 (P = 0.031);Loss of phosphorylation at Y27 (P = 0.031);Loss of phosphorylation at Y27 (P = 0.031);
MVP		0.61
ClinPred		0.59	D
GERP RS		4.7
Varity_R		0.10
gMVP		0.52

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

Other links and lift over

dbSNP: rs1927847782; hg19: chrX-46845146;