4-128846425-G-C

Position:

• chr4-128846425-G-C

Variant summary

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

The NM_199320.4(JADE1):​c.189G>C​(p.Gln63His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JADE1 NM_199320.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23784304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JADE1	NM_199320.4	c.189G>C	p.Gln63His	missense_variant	4/11	ENST00000226319.11	NP_955352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JADE1	ENST00000226319.11	c.189G>C	p.Gln63His	missense_variant	4/11	5	NM_199320.4	ENSP00000226319.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 30, 2024

The c.189G>C (p.Q63H) alteration is located in exon 4 (coding exon 3) of the JADE1 gene. This alteration results from a G to C substitution at nucleotide position 189, causing the glutamine (Q) at amino acid position 63 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	0.24
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.;.;T;T;T;T;T;.;T;T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;D;.;D;D;D;.;D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L;L;L;.;L;.;L;.;L;.;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N;.;N;N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.24	T;T;T;T;T;T;.;T;T;T;.;T
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0	D;B;P;.;D;.;D;.;B;.;D;.
Vest4		0.30
MutPred		0.49		Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);Gain of glycosylation at Y62 (P = 0.0153);
MVP		0.49
MPC		1.5
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.19
gMVP		0.73

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: rs1041995022; hg19: chr4-129767580;