20-10658611-C-G

Variant names:

• chr20-10658611-C-G
• NM_000214.3:c.551G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000214.3(JAG1):​c.551G>C​(p.Arg184Pro) 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. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.90

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a strand (size 13) in uniprot entity JAG1_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000214.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in the JAG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 65 curated benign missense variants. Gene score misZ: 3.2459 (above the threshold of 3.09). Trascript score misZ: 5.2848 (above the threshold of 3.09). GenCC associations: The gene is linked to tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.551G>C	p.Arg184Pro	missense_variant	Exon 4 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.551G>C	p.Arg184Pro	missense_variant	Exon 4 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.417G>C		non_coding_transcript_exon_variant	Exon 2 of 25	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Arteriohepatic dysplasia Other:1

-

Gilbert/Spinner Lab, Children's Hospital of Philadelphia

Significance: not provided

Review Status: no classification provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.83		Loss of catalytic residue at R184 (P = 0.1011);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-10639259;