4-128871702-G-C

Variant names:

• chr4-128871702-G-C
• rs563173857
• NM_199320.4:c.1969G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_199320.4(JADE1):​c.1969G>C​(p.Gly657Arg) 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 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JADE1 NM_199320.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

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]

SCLT1 (HGNC:26406): (sodium channel and clathrin linker 1) This gene encodes an adaptor protein. Studies of a related gene in rat suggest that the encoded protein functions to link clathrin to the sodium channel protein type 10 subunit alpha protein. The encoded protein has also been identified as a component of distal appendages of centrioles that is necessary for ciliogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

SCLT1 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• retinitis pigmentosa

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• Senior-Loken syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049693346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199320.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JADE1	NM_199320.4	MANE Select	c.1969G>C	p.Gly657Arg	missense	Exon 11 of 11	NP_955352.1	Q6IE81-1
	JADE1	NM_001287439.2		c.1969G>C	p.Gly657Arg	missense	Exon 11 of 11	NP_001274368.1	Q6IE81-1
	JADE1	NM_001287440.2		c.1969G>C	p.Gly657Arg	missense	Exon 11 of 11	NP_001274369.1	Q6IE81-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JADE1	ENST00000226319.11	TSL:5 MANE Select	c.1969G>C	p.Gly657Arg	missense	Exon 11 of 11	ENSP00000226319.6	Q6IE81-1
	JADE1	ENST00000947587.1		c.2068G>C	p.Gly690Arg	missense	Exon 11 of 11	ENSP00000617646.1
	JADE1	ENST00000887597.1		c.2041G>C	p.Gly681Arg	missense	Exon 12 of 12	ENSP00000557656.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.050
Sift	Benign	0.50	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.31		Loss of ubiquitination at K658 (P = 0.0345)
MVP		0.27
MPC		0.83
ClinPred		0.066	T
GERP RS		3.7
Varity_R		0.027
gMVP		0.21
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs563173857; hg19: chr4-129792857;