chr20-10650275-T-TG

Position:

• chr20-10650275-T-TG

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.1205dupC​(p.Gln403fs) 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:3
• Conservation: PhyloP100: 8.11

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 (HGNC:):

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 20-10650275-T-TG is Pathogenic according to our data. Variant chr20-10650275-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 213558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.1205dupC	p.Gln403fs	frameshift_variant	9/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.1205dupC	p.Gln403fs	frameshift_variant	9/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.1071dupC		non_coding_transcript_exon_variant	7/25	2
JAG1	ENST00000617965.2	n.1794dupC		non_coding_transcript_exon_variant	3/17	5
JAG1	ENST00000622545.1	n.-20dupC		upstream_gene_variant		5		ENSP00000484139.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 10, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 213558). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 9585603). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln403Thrfs*13) 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2014

The c.1205dupC mutation in the JAG1 gene has been reported previously in association with Alagille syndrome using different nomenclature (Krantz, et al., 1998) . The duplication causes a frameshift starting with codon Glycine 403, changes this amino acid to a Threonine residue and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Gln403ThrfsX13. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay This variant was found in JAG1 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35615084; hg19: chr20-10630923;