rs1555827769

Positions:

• chr20-10641587-CAGGGGTGGACGAAGC-CTGCCCTGG

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PVS1 PS1 PM2 PP2 PP5_Moderate

The NM_000214.3(JAG1):​c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA​(p.Cys925fs) variant causes a frameshift, missense 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000214.3 (JAG1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAG1. . Gene score misZ 3.2459 (greater than the threshold 3.09). Trascript score misZ 5.2848 (greater than threshold 3.09). GenCC has associacion of gene with tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.
• PP5: Variant 20-10641588-AGGGGTGGACGAAGC-TGCCCTGG is Pathogenic according to our data. Variant chr20-10641588-AGGGGTGGACGAAGC-TGCCCTGG is described in ClinVar as [Pathogenic]. Clinvar id is 536527.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA	p.Cys925fs	frameshift_variant, missense_variant	23/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA	p.Cys925fs	frameshift_variant, missense_variant	23/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.2640_2654delGCTTCGTCCACCCCTinsCCAGGGCA		non_coding_transcript_exon_variant	21/25	2
JAG1	ENST00000617965.2	n.3363_3377delGCTTCGTCCACCCCTinsCCAGGGCA		non_coding_transcript_exon_variant	17/17	5

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). This variant has been reported in an individual affected with Alagille syndrome (PMID: 16575836). This variant is also known as c.2773_2787delinsCCAGGGCA in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys925Serfs*18) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. -

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: rs1555827769; hg19: chr20-10622236;