4-128849027-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_199320.4(JADE1):c.344A>G(p.Tyr115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: JADE1 NM_199320.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

JADE1 (HGNC:30027): (jade family PHD finger 1) Enables transcription coactivator activity. Involved in histone acetylation and negative regulation of canonical Wnt signaling pathway. Acts upstream of or within negative regulation of G1/S transition of mitotic cell cycle. Located in several cellular components, including ciliary basal body; cytosol; and nuclear speck. Part of histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, JADE1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JADE1	NM_199320.4	c.344A>G	p.Tyr115Cys	missense_variant	5/11	ENST00000226319.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JADE1	ENST00000226319.11	c.344A>G	p.Tyr115Cys	missense_variant	5/11	5	NM_199320.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251430 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135896

Gnomad AFR exome AF: 0.00

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727222

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Dec 28, 2022

The c.344A>G (p.Y115C) alteration is located in exon 5 (coding exon 4) of the JADE1 gene. This alteration results from a A to G substitution at nucleotide position 344, causing the tyrosine (Y) at amino acid position 115 to be replaced by a cysteine (C). 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	0.15
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;T;T;T;T;T;.;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;.;D;D;.;D;.;D;D;D;.;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M;M;.;.;M;.;M;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;.;D;D;D;.;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D;D;D;D;D;D;.;D;D;D;.;D
Sift4G	Uncertain	0.052	T;D;D;T;T;T;T;T;D;T;T;D
Polyphen		0.99	D;D;D;.;D;.;D;.;D;.;D;.
Vest4		0.73
MutPred		0.70		Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);.;Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);Gain of glycosylation at Y115 (P = 0.0194);
MVP		0.41
MPC		1.8
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.91

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

Other links and lift over

dbSNP: rs747883572; hg19: chr4-129770182;