20-10643818-G-T

Position:

• chr20-10643818-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000214.3(JAG1):​c.2418C>A​(p.Cys806Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAG1 NM_000214.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.289

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 20-10643818-G-T is Pathogenic according to our data. Variant chr20-10643818-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 234518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10643818-G-T is described in Lovd as [Pathogenic]. Variant chr20-10643818-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2418C>A	p.Cys806Ter	stop_gained	20/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2418C>A	p.Cys806Ter	stop_gained	20/26	1	NM_000214.3	ENSP00000254958	P1
JAG1	ENST00000423891.6	n.2284C>A		non_coding_transcript_exon_variant	18/25	2
JAG1	ENST00000617965.2	n.3007C>A		non_coding_transcript_exon_variant	14/17	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2019

Nonsense 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11180599, 11139239) -

Alagille syndrome due to a JAG1 point mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2016

For these reasons, this variant has been classified as Pathogenic. Truncating variants in JAG1 are known to be pathogenic (PMID: 11180599, 12497640). This particular variant was observed de novo in an individual with Alagille syndrome (PMID: 11180599). This sequence change creates a premature translational stop signal at codon 806 (p.Cys806*) of the JAG1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Benign	0.014
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.79	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.78		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs533306015; hg19: chr20-10624466;