rs727504412

Positions:

• chr20-10645244-CACTG-C

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.Gln708fs) 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/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2122_2125delCAGT	p.Gln708fs	frameshift_variant	17/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2122_2125delCAGT	p.Gln708fs	frameshift_variant	17/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.1988_1991delCAGT		non_coding_transcript_exon_variant	15/25	2
JAG1	ENST00000488480.2	n.519_522delCAGT		non_coding_transcript_exon_variant	3/4	4
JAG1	ENST00000617965.2	n.2711_2714delCAGT		non_coding_transcript_exon_variant	11/17	5

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

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Aug 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -

Alagille syndrome due to a JAG1 point mutation Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 16, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Istanbul Faculty of Medicine, Istanbul University	Nov 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Arteriohepatic dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Nov 09, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 09, 2011

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 14, 2019

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;