rs727504412

Variant names:

• chr20-10645244-CACTG-C
• rs727504412
• NM_000214.3:c.2122_2125delCAGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000214.3(JAG1):​c.2122_2125delCAGT​(p.Gln708ValfsTer34) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JAG1 NM_000214.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 10.0

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 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 20-10645244-CACTG-C is Pathogenic according to our data. Variant chr20-10645244-CACTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 177941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10645244-CACTG-C is described in Lovd as [Pathogenic]. Variant chr20-10645244-CACTG-C is described in Lovd as [Pathogenic]. Variant chr20-10645244-CACTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2122_2125delCAGT	p.Gln708ValfsTer34	frameshift_variant	Exon 17 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2122_2125delCAGT	p.Gln708ValfsTer34	frameshift_variant	Exon 17 of 26	1	NM_000214.3	ENSP00000254958.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Feb 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15712272, 10220506, 33142350, 24748328, 25676721, 12442286, 22488849, 9207788) -

Apr 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 17, 2017

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: 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

- -

Alagille syndrome due to a JAG1 point mutation Pathogenic:4

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln708Valfs*34) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Alagille syndrome (PMID: 9207788, 12442286, 15712272, 22488849, 25676721). This variant is also known as c.2531_2534delCAGT. ClinVar contains an entry for this variant (Variation ID: 177941). For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 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

- -

Aug 16, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2022

Istanbul Faculty of Medicine, Istanbul University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Arteriohepatic dysplasia Pathogenic:1

Nov 09, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for a 4bp deletion, c.2122_2125del, in the JAG1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Gln708Valfs*34) and may result in a null allele due to nonsense-mediated mRNA decay. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been previously reported in multiple patients with with Alagille syndrome (Jurkiewicz et al Hum Mutat. 2005 Mar;25(3):321 and also see ClinVar https://www.ncbi.nlm.nih.gov/clinvar/variation/177941/) . This variant is considered to be a pathogenic according to the ACMG guidelines (evidence used: PVS1, PM2, PP5). -

Arteriohepatic dysplasia;CN130023:Heart, malformation of Pathogenic:1

Mar 09, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln708fs variant is predicted to cause a frameshift, which alters the protei n's amino acid sequence beginning at codon 708 and leads to a premature stop cod on 34 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein (loss of function). This variant has been reported in o ne child with Alagille syndrome as well as the mildly affected mother. Absence from 100 healthy control chromosomes supports a pathogenic role (Li 1997, varian t reported as 2531del4). In addition, it was reported as de novo in 5 additional , unrelated individuals with Alagille syndrome (Crosnier 1999 - variant reported as 2535-2538delCAGT). Loss of function is an established mechanism of disease f or the JAG1 gene and is typically associated with Alagille syndrome (GeneReviews ). In summary, the Gln708fs variant meets our criteria for pathogenicity (http:/ /pcpgm.partners.org/LMM) and is highly likely to be causative for disease. -

JAG1-related disorder Pathogenic:1

Dec 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The JAG1 c.2122_2125delCAGT variant is predicted to result in a frameshift and premature protein termination (p.Gln708Valfs*34). This variant has been reported to be causative for Alagille syndrome (Li et al 1997. PubMed ID: 9207788; Jurkiewicz et al. 2005. PubMed ID: 15712272; Table 2, Qiao et al. 2021. PubMed ID: 33142350). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Tetralogy of Fallot Pathogenic:1

May 14, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -

Computational scores

Source: dbNSFP v4.3

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: rs727504412; hg19: chr20-10625892;