20-10652589-G-C

Position:

• chr20-10652589-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000214.3(JAG1):​c.765C>G​(p.Tyr255*) 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 (★). Synonymous variant affecting the same amino acid position (i.e. Y255Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: JAG1 NM_000214.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.608

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 12 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 20-10652589-G-C is Pathogenic according to our data. Variant chr20-10652589-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 234555.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-10652589-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.765C>G	p.Tyr255*	stop_gained	6/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.765C>G	p.Tyr255*	stop_gained	6/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.631C>G		non_coding_transcript_exon_variant	4/25	2
JAG1	ENST00000617965.2	n.134C>G		non_coding_transcript_exon_variant	1/17	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2015

The Y255X nonsense pathogenic variant in the JAG1 gene has been reported previously in association with Alagille syndrome (Witt et al., 2004; Warthen et al., 2006). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and functional studies have shown that Y255X results in the loss of mRNA expression (Boyer et al., 2005). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, another nucleotide substitution (c.765 C>A), which leads to the same nonsense change (Y255X), has been reported as pathogenic in association with Alagille syndrome (Kola et al., 2011). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Benign	-0.70
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.36	N
Vest4		0.95
GERP RS		-12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1131695; hg19: chr20-10633237;