rs1555827653

chr20-10640814-TCTTA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000214.3(JAG1):c.3164_3167del(p.Val1055GlufsTer7) 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 (★★).

• 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: 8.95

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-10640814-TCTTA-T is Pathogenic according to our data. Variant chr20-10640814-TCTTA-T is described in ClinVar as [Pathogenic]. Clinvar id is 497597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10640814-TCTTA-T is described in Lovd as [Pathogenic]. Variant chr20-10640814-TCTTA-T is described in Lovd as [Pathogenic]. Variant chr20-10640814-TCTTA-T is described in Lovd as [Pathogenic]. Variant chr20-10640814-TCTTA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.3164_3167del	p.Val1055GlufsTer7	frameshift_variant	25/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.3164_3167del	p.Val1055GlufsTer7	frameshift_variant	25/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.3030_3033del		non_coding_transcript_exon_variant	23/25	2
JAG1	ENST00000617357.1	n.459_462del		non_coding_transcript_exon_variant	1/2	2

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

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	Frameshift variant predicted to result in protein truncation, as the last 164 amino acids are replaced with 6 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31160058, 32369273, 17949281, 11139247, 10220506, 31343788, 29555955, 25676721) -

Alagille syndrome due to a JAG1 point mutation Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2018	For these reasons, this variant has been classified as Pathogenic. This variant results in the deletion of the entire transmembrane domain of the JAG1 protein and should render it unable to attach to the cytoplasmic membrane (PMID: 26548814). This variant has been reported in individuals affected with Alagille syndrome, being found to be de novo in one case (PMID: 25676721, 10220506). This variant is also known as 3577–3580delTAAG in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the JAG1 gene (p.Val1055Glufs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 164 amino acids of the JAG1 protein. Other truncating variants downstream of p.Val1055Glufs*7 have been reported to be de novo in Allagile syndrome cases (PMID: 26076142). This suggests that deletion of this region of the JAG1 protein is causative of disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555827653; hg19: chr20-10621462;