rs121918350

Positions:

• chr20-10658612-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000214.3(JAG1):​c.550C>T​(p.Arg184Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.05

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a strand (size 13) in uniprot entity JAG1_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000214.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.978
• PP5: Variant 20-10658612-G-A is Pathogenic according to our data. Variant chr20-10658612-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658612-G-A is described in Lovd as [Pathogenic]. Variant chr20-10658612-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.550C>T	p.Arg184Cys	missense_variant	4/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.550C>T	p.Arg184Cys	missense_variant	4/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.416C>T		non_coding_transcript_exon_variant	2/25	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.550C>T (p.Arg184Cys) in JAG1 gene has been reported in affected individuals in the literature (Crosnier C et.al.,2001). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg184Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 184 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg184Cys in JAG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the JAG1 protein (p.Arg184Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Alagille syndrome (PMID: 9585603, 22405927). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7619). Advanced 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 at Invitae 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. This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10220506, 10533065, 22487239, 24748328). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 17, 2017

- -

JAG1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2024

The JAG1 c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant has been reported with de novo occurrence in at least two patients with Alagille syndrome (see example: Table 2, Krantz et al. 1998. PubMed ID: 9585603; Table 2, Li et al. 2015. PubMed ID: 26076142). To our knowledge, this variant has not been reported in a large population database, indicating it is rare. In addition, different variants affecting the same amino acid (Arg184Gly, Arg184His) have also been reported to be pathogenic for Alagille syndrome (Krantz et al. 1998. PubMed ID: 9585603; Crosnier et al. 1999. PubMed ID: 10220506). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Loss of catalytic residue at R184 (P = 0.1998);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.92

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: rs121918350; hg19: chr20-10639260;