rs1060501350

Positions:

• chr20-10641688-C-G
• chr20-10641688-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000214.3(JAG1):​c.2688G>C​(p.Trp896Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W896L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56

Genes affected

JAG1 (HGNC:6188): (jagged canonical Notch ligand 1) The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAG1. . Gene score misZ 3.2459 (greater than the threshold 3.09). Trascript score misZ 5.2848 (greater than threshold 3.09). GenCC has associacion of gene with tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.2688G>C	p.Trp896Cys	missense_variant	23/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.2688G>C	p.Trp896Cys	missense_variant	23/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.2554G>C		non_coding_transcript_exon_variant	21/25	2
JAG1	ENST00000617965.2	n.3277G>C		non_coding_transcript_exon_variant	17/17	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.2	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.71		Gain of disorder (P = 0.0058);
MVP		0.75
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-10622336;