chr20-10658611-C-T

Variant names:

• chr20-10658611-C-T
• rs121918351
• NM_000214.3:c.551G>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.551G>A​(p.Arg184His) 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 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)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:2
• Conservation: PhyloP100: 7.90

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 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 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: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 20-10658611-C-T is Pathogenic according to our data. Variant chr20-10658611-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10658611-C-T is described in Lovd as [Pathogenic]. Variant chr20-10658611-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.551G>A	p.Arg184His	missense_variant	Exon 4 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.551G>A	p.Arg184His	missense_variant	Exon 4 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.417G>A		non_coding_transcript_exon_variant	Exon 2 of 25	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:4 Other:1

Feb 04, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3, PM5_STR, PS4_MOD, PM2_SUP, PP2, PP3 -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alagille syndrome (PMID: 9585603, 10220506, 12442286, 24748328, 25676721). ClinVar contains an entry for this variant (Variation ID: 7620). 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) performed at Invitae indicates that this missense variant is expected to disrupt JAG1 protein function. Experimental studies have shown that this missense change affects JAG1 function (PMID: 11058898, 22487239). This variant disrupts the p.Arg184 amino acid residue in JAG1. Other variant(s) that disrupt this residue have been observed in individuals with JAG1-related conditions (PMID: 10220506, 10533065), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 184 of the JAG1 protein (p.Arg184His). -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 15, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 07, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation;C5562003:Charcot-Marie-Tooth disease, axonal, Type 2HH Pathogenic:1

Jul 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arteriohepatic dysplasia Other:1

-

Gilbert/Spinner Lab, Children's Hospital of Philadelphia

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.81		Gain of catalytic residue at V185 (P = 0.3137);
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.77

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: rs121918351; hg19: chr20-10639259; COSMIC: COSV54757968;