rs1555829660
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000214.3(JAG1):c.634T>C(p.Cys212Arg) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C212S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000214.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.634T>C | p.Cys212Arg | missense_variant | 4/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.634T>C | p.Cys212Arg | missense_variant | 4/26 | 1 | NM_000214.3 | P1 | |
JAG1 | ENST00000423891.6 | n.500T>C | non_coding_transcript_exon_variant | 2/25 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 24, 2017 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Family studies have indicated that this variant was not present in the parents of an individual affected with JAG1-related disease which suggests that it was de novo in that affected individual (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 212 of the JAG1 protein (p.Cys212Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at