chr20-10656450-G-A

Position:

• chr20-10656450-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000214.3(JAG1):​c.703C>T​(p.Arg235*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JAG1 NM_000214.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.61

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 18 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 20-10656450-G-A is Pathogenic according to our data. Variant chr20-10656450-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 234320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10656450-G-A is described in Lovd as [Pathogenic]. Variant chr20-10656450-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3	c.703C>T	p.Arg235*	stop_gained	5/26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.703C>T	p.Arg235*	stop_gained	5/26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.569C>T		non_coding_transcript_exon_variant	3/25	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461504 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	Nonsense variant predicted to result in 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: 25525159, 24748328, 27256232, 11139247, 26076142, 9585603, 29707407, 11180599, 31343788) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratoire de Génétique Moléculaire, CHU Bordeaux	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2018	- -

Alagille syndrome due to a JAG1 point mutation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 05, 2021	PVS1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 05, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 234320). This premature translational stop signal has been observed in individual(s) with Alagille syndrome (PMID: 9585603, 23891399, 24748328, 26076142). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg235*) in the JAG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in JAG1 are known to be pathogenic (PMID: 11180599). -

JAG1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2023

The JAG1 c.703C>T variant is predicted to result in premature protein termination (p.Arg235*). This variant has been previously reported in individuals with Alagille syndrome, in some cases occurring de novo (see for example Krantz et al. 1998. PubMed ID: 9585603; Colliton et al. 2001. PubMed ID: 11180599; Jurkiewicz et al 2014. PubMed ID: 24748328). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.94
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs876660980; hg19: chr20-10637098; COSMIC: COSV54761406; COSMIC: COSV54761406;