chr20-10648631-CAG-C

Variant names:

• chr20-10648631-CAG-C
• rs876660981
• NM_000214.3:c.1485_1486delCT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000214.3(JAG1):​c.1485_1486delCT​(p.Cys496PhefsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.32
• Publications: 6 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-10648631-CAG-C is Pathogenic according to our data. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10648631-CAG-C is described in CliVar as Pathogenic. Clinvar id is 234321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.1485_1486delCT	p.Cys496PhefsTer9	frameshift_variant	Exon 12 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.1485_1486delCT	p.Cys496PhefsTer9	frameshift_variant	Exon 12 of 26	1	NM_000214.3	ENSP00000254958.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 21, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1485_1486delCT pathogenic variant in the JAG1 gene has been reported previously in association with Alagille syndrome (Jurkiewicz et al., 2005; Crosnier et al., 1999). The c.1485_1486delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The deletion causes a frameshift starting with codon Cysteine 496, changes this amino acid to a Phenylalanine residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Cys496PhefsX9. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

JAG1: PVS1, PM2, PS4:Moderate -

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alagille syndrome due to a JAG1 point mutation Pathogenic:1

Sep 15, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Tetralogy of Fallot Pathogenic:1

May 26, 2023

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs876660981; hg19: chr20-10629279;