Genetic Variant NM_000214.3:c.2230C>T (chr20-10644977-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000214.3(JAG1):c.2230C>T(p.Arg744*) variant causes a stop gained, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

JAG1
NM_000214.3 stop_gained, splice_region

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.07

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 20-10644977-G-A is Pathogenic according to our data. Variant chr20-10644977-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 213538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10644977-G-A is described in Lovd as [Pathogenic]. Variant chr20-10644977-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.2230C>T	p.Arg744*	stop_gained, splice_region_variant	Exon 18 of 26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 link	c.2230C>T	p.Arg744*	stop_gained, splice_region_variant	Exon 18 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 link	n.2096C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 25	2
JAG1	ENST00000488480.2 link	n.627C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4
JAG1	ENST00000617965.2 link	n.2819C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 12 of 17	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726920

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation

Pathogenic:4

Jan 16, 2024

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.Arg744*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Allagile syndrome (PMID: 17241866, 21752016, 24748328). ClinVar contains an entry for this variant (Variation ID: 213538). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4+PM6 -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000213538 / PMID: 9585603). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:3

Oct 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in multiple additional individuals with Alagille syndrome (Onouchi et al., 1999; Colliton et al., 2001; Guegan et al., 2012; Rocha et al., 2012; Jurkiewicz et al., 2014); 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 (gnomAD); This variant is associated with the following publications: (PMID: 11180599, 21752016, 22759690, 24748328, 25525159, 34185059, 34071626, 9585603, 10429362) -

May 24, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM6, PS4_moderate, PVS1 -

JAG1-related disorder

Pathogenic:1

Oct 23, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The JAG1 c.2230C>T variant is predicted to result in premature protein termination (p.Arg744*). This variant has been reported to be causative for Alagille syndrome (described as R739X, Krantz et al. 1998. PubMed ID: 9585603; Guegan et al. 2011. PubMed ID: 21752016; Jurkiewicz et al. 2014. PubMed ID: 24748328). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. Nonsense variants in JAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation;C5562003:Charcot-Marie-Tooth disease, axonal, Type 2HH

Pathogenic:1

Feb 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.92

Vest4

0.98

GERP RS

4.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over