rs863223650

Variant names:

• chr20-10650325-C-T
• rs863223650
• NM_000214.3:c.1156G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000214.3(JAG1):​c.1156G>A​(p.Gly386Arg) 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a disulfide_bond (size 11) in uniprot entity JAG1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000214.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the JAG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 65 curated benign missense variants. Gene score misZ: 3.2459 (above the threshold of 3.09). Trascript score misZ: 5.2848 (above the threshold of 3.09). GenCC associations: The gene is linked to tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-10650325-C-T is Pathogenic according to our data. Variant chr20-10650325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10650325-C-T is described in Lovd as [Pathogenic]. Variant chr20-10650325-C-T is described in Lovd as [Pathogenic]. Variant chr20-10650325-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.1156G>A	p.Gly386Arg	missense_variant	Exon 9 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.1156G>A	p.Gly386Arg	missense_variant	Exon 9 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.1022G>A		non_coding_transcript_exon_variant	Exon 7 of 25	2
JAG1	ENST00000617965.2	n.1745G>A		non_coding_transcript_exon_variant	Exon 3 of 17	5
JAG1	ENST00000622545.1	n.-69G>A		upstream_gene_variant		5		ENSP00000484139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:3

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 386 of the JAG1 protein (p.Gly386Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alagille syndrome (PMID: 11058898, 22405927, 22488849, 24748328, 26076142). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 213531). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on JAG1 protein function. Experimental studies have shown that this missense change does not substantially affect JAG1 function (PMID: 22487239). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 13, 2022

Institute of Medical Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.1156G>A (p.Gly386Arg) in JAG1 gene has been reported in heterozygous state to be de novo in several individuals affected with Alagille syndrome (Lin HC et al.). Experimental studies have shown that this missense change has no impact on protein processing, subcellular localization or protein transactivation in vitro (Tada M et al.). The p.Gly386Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. This sequence change replaces glycine with arginine at codon 386 of the JAG1 protein (p.Gly386Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. The amino acid change p.Gly386Arg in JAG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

JAG1-related disorder Pathogenic:1

Nov 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The JAG1 c.1156G>A variant is predicted to result in the amino acid substitution p.Gly386Arg. This variant has been reported in individuals with Alagille syndrome (Heritage et al. 2000. PubMed ID: 11058898; Jurkiewicz et al. 2014. PubMed ID: 24748328; Li et al. 2015. PubMed ID: 26076142; Liu et al. 2018. PubMed ID: 30074189). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Loss of catalytic residue at G387 (P = 0.0576);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: -2
DS_AL_spliceai		0.70		Position offset: 35

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863223650; hg19: chr20-10630973; COSMIC: COSV99653714; COSMIC: COSV99653714;