rs886039393

Positions:

• chr20-10645368-TCTTTC-T

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.2096_2100del​(p.Gly699AspfsTer6) 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:4
• Conservation: PhyloP100: 8.02

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 20-10645368-TCTTTC-T is Pathogenic according to our data. Variant chr20-10645368-TCTTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 7621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10645368-TCTTTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2096_2100del	p.Gly699AspfsTer6	frameshift_variant	16/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2096_2100del	p.Gly699AspfsTer6	frameshift_variant	16/26	1	NM_000214.3	ENSP00000254958	P1

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 21, 2017	Loss-of-function variants in JAG1 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with Alagille syndrome (PMID: 9585603). It is also called 2504del5 in the literature. For these reasons, this variant has been classified as Pathogenic. This sequence change deletes 5 nucleotides from exon 16 of the JAG1 mRNA (c.2096_2100delGAAAG), causing a frameshift at codon 699. This creates a premature translational stop signal (p.Gly699Aspfs*6) and is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2022	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9585603) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039393; hg19: chr20-10626016;