rs876661121

Variant names:

• chr20-10641112-C-A
• rs876661121
• NM_000214.3:c.3048+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10641112-C-A
• chr20-10641112-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000214.3(JAG1):​c.3048+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.38

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03609516 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-10641112-C-A is Pathogenic according to our data. Variant chr20-10641112-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234615.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=2}. Variant chr20-10641112-C-A is described in Lovd as [Pathogenic]. Variant chr20-10641112-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.3048+1G>T		splice_donor_variant, intron_variant	Intron 24 of 25	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.3048+1G>T		splice_donor_variant, intron_variant	Intron 24 of 25	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000617357.1	n.165G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
JAG1	ENST00000423891.6	n.2914+1G>T		splice_donor_variant, intron_variant	Intron 22 of 24	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Mar 29, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3048+1 G>T splice site variant in the JAG1 gene has been previously reported in association with Alagille syndrome (Warthen et al., 2006). This pathogenic variant destroys the canonical splice donor site in intron 24, and causes abnormal gene splicing (Boyer et al., 2005). Additionally, 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. Therefore, the presence of this pathogenic variant is consistent with a diagnosis of Alagille syndrome. -

Sep 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alagille syndrome due to a JAG1 point mutation Pathogenic:1 Uncertain:1

Feb 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 24 of the JAG1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Alagille syndrome (PMID: 15772854). ClinVar contains an entry for this variant (Variation ID: 234615). Studies have shown that disruption of this splice site results in skipping of exon 24, but is expected to preserve the integrity of the reading-frame (PMID: 15772854). This variant disrupts a region of the JAG1 protein in which other variant(s) (p.Cys1002Arg) have been observed in individuals with JAG1-related conditions (PMID: 31343788). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice donor c.3048+1G>T variant in the JAG2 gene has been previously reported in association with Alagille syndrome (Gilbert, Melissa A et al., 2019). The variant is absent in gnomAD Exomes and 1000 Genomes. It is submitted to ClinVar database as Pathogenic. The variant affects the GT donor splice site downstream of exon 24. It is present in the penultimate intron and so functional studies are required to prove the pathogenicity of the variant. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		6.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs876661121; hg19: chr20-10621760;