rs1555827769

Variant names:

• chr20-10641588-AGGGGTGGACGAAGC-TGCCCTGG
• rs1555827769
• NM_000214.3:c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA

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.Cys925SerfsTer18) 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 the same amino acid substitution has been previously reported as Pathogenic in 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]

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 the JAG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 65 curated benign missense variants. Gene score misZ: 3.2459 (above the threshold of 3.09). Trascript score misZ: 5.2848 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA	p.Cys925SerfsTer18	frameshift_variant, missense_variant	Exon 23 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2774_2788delGCTTCGTCCACCCCTinsCCAGGGCA	p.Cys925SerfsTer18	frameshift_variant, missense_variant	Exon 23 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.2640_2654delGCTTCGTCCACCCCTinsCCAGGGCA		non_coding_transcript_exon_variant	Exon 21 of 25	2
JAG1	ENST00000617965.2	n.3363_3377delGCTTCGTCCACCCCTinsCCAGGGCA		non_coding_transcript_exon_variant	Exon 17 of 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

Oct 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). 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. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). For these reasons, this variant has been classified as Pathogenic. -

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;