chr4-128871718-A-G

Position:

• chr4-128871718-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_199320.4(JADE1):​c.1985A>G​(p.Asn662Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,614,130 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (115 hom.)
• Consequence: JADE1 NM_199320.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014033616).
• BP6: Variant 4-128871718-A-G is Benign according to our data. Variant chr4-128871718-A-G is described in ClinVar as [Benign]. Clinvar id is 776019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JADE1	NM_199320.4	c.1985A>G	p.Asn662Ser	missense_variant	11/11	ENST00000226319.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JADE1	ENST00000226319.11	c.1985A>G	p.Asn662Ser	missense_variant	11/11	5	NM_199320.4	P1

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3403 AN: 152162 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00677 AC: 1699 AN: 250942 Hom.: 54 AF XY: 0.00549 AC XY: 745 AN XY: 135610

Gnomad AFR exome AF: 0.0735

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.00666

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000962

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00328 AC: 4793 AN: 1461850 Hom.: 115 Cov.: 32 AF XY: 0.00318 AC XY: 2312 AN XY: 727228

Gnomad4 AFR exome AF: 0.0773

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00176

Gnomad4 SAS exome AF: 0.00666

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000789

Gnomad4 OTH exome AF: 0.00694

GnomAD4 genome AF: 0.0225 AC: 3421 AN: 152280 Hom.: 110 Cov.: 32 AF XY: 0.0221 AC XY: 1646 AN XY: 74470

Gnomad4 AFR AF: 0.0737

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00502 Hom.: 24

Bravo AF: 0.0250

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0747 AC: 329

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00786 AC: 954

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.77
DEOGEN2	Benign	0.026	T;.;T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.85	T;T;.;.;.
MetaRNN	Benign	0.0014	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.;N;N;N
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.12	N;N;N;.;.
REVEL	Benign	0.072
Sift	Benign	0.85	T;T;T;.;.
Sift4G	Benign	0.81	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.041
MVP		0.34
MPC		0.55
ClinPred		0.0049	T
GERP RS		2.3
Varity_R		0.020
gMVP		0.085

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: rs6855813; hg19: chr4-129792873;