chr4-128871632-A-C

Variant names:

• chr4-128871632-A-C
• rs6850940
• NM_199320.4:c.1899A>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.1899A>C​(p.Leu633Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 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. Synonymous variant affecting the same amino acid position (i.e. L633L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JADE1 NM_199320.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700
• Publications: 3 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=0.037981182).

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.1899A>C	p.Leu633Phe	missense	Exon 11 of 11	NP_955352.1	Q6IE81-1
	JADE1	NM_001287439.2		c.1899A>C	p.Leu633Phe	missense	Exon 11 of 11	NP_001274368.1	Q6IE81-1
	JADE1	NM_001287440.2		c.1899A>C	p.Leu633Phe	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.1899A>C	p.Leu633Phe	missense	Exon 11 of 11	ENSP00000226319.6	Q6IE81-1
	JADE1	ENST00000947587.1		c.1998A>C	p.Leu666Phe	missense	Exon 11 of 11	ENSP00000617646.1
	JADE1	ENST00000887597.1		c.1971A>C	p.Leu657Phe	missense	Exon 12 of 12	ENSP00000557656.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250830 AF XY: 0.00000738

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.32
DANN	Benign	0.54
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.070
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.054
MutPred		0.31		Gain of glycosylation at S629 (P = 0.0794)
MVP		0.10
MPC		0.76
ClinPred		0.038	T
GERP RS		-4.7
Varity_R		0.020
gMVP		0.18
Mutation Taster		=91/9	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: rs6850940; hg19: chr4-129792787;