rs1555828546

Variant names:

• chr20-10647966-AG-A
• NM_000214.3:c.1713delC

Your query was ambiguous. Multiple possible variants found:

• chr20-10647966-AG-A
• chr20-10647966-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000214.3(JAG1):​c.1713delC​(p.Cys572ValfsTer3) variant causes a frameshift change involving the alteration of a non-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, single submitter P:2
• Conservation: PhyloP100: 0.0310

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 12 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 20-10647966-AG-A is Pathogenic according to our data. Variant chr20-10647966-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2444244.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-10647966-AG-A is described in Lovd as [Pathogenic]. Variant chr20-10647966-AG-A is described in Lovd as [Pathogenic]. Variant chr20-10647966-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.1713delC	p.Cys572ValfsTer3	frameshift_variant	Exon 13 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.1713delC	p.Cys572ValfsTer3	frameshift_variant	Exon 13 of 26	1	NM_000214.3	ENSP00000254958.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:1

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with JAG1 related disorder (PMID: 16575836). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

JAG1-related disorder Pathogenic:1

Aug 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The JAG1 c.1713delC variant is predicted to result in a frameshift and premature protein termination (p.Cys572Valfs*3). This variant has been reported as causative for Alagille syndrome (Warthen et al. 2006. PubMed ID: 16575836; Gilbert et al. 2019. PubMed ID: 31343788). 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. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-10628614;