chr20-10652503-C-T

Variant names:

• chr20-10652503-C-T
• rs1555829067
• NM_000214.3:c.851G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000214.3(JAG1):​c.851G>A​(p.Cys284Tyr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C284S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

JAG1 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.851G>A	p.Cys284Tyr	missense	Exon 6 of 26	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.851G>A	p.Cys284Tyr	missense	Exon 6 of 26	ENSP00000254958.4
	JAG1	ENST00000423891.6	TSL:2	n.717G>A		non_coding_transcript_exon	Exon 4 of 25
	JAG1	ENST00000617965.2	TSL:5	n.220G>A		non_coding_transcript_exon	Exon 1 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

JAG1-related disorder Uncertain:1

Jul 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The JAG1 c.851G>A variant is predicted to result in the amino acid substitution p.Cys284Tyr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, a different change affecting the same codon (c.851G>T, p.Cys284Phe) has been reported to cause Alagille syndrome (Crosnier et al. 1999. PubMed ID: 10220506; Boyer-Di Ponio et al. 2007. PubMed ID: 17720887). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.97		Loss of catalytic residue at T286 (P = 0.0964)
MVP		0.99
MPC		3.0
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs1555829067; hg19: chr20-10633151;