20-10644907-G-C

Variant names:

• chr20-10644907-G-C
• NM_000214.3:c.2300C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000214.3(JAG1):​c.2300C>G​(p.Thr767Arg) variant causes a missense change. 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T767T) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 15) in uniprot entity JAG1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000214.3
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.2300C>G	p.Thr767Arg	missense_variant	Exon 18 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.2300C>G	p.Thr767Arg	missense_variant	Exon 18 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.2166C>G		non_coding_transcript_exon_variant	Exon 16 of 25	2
JAG1	ENST00000488480.2	n.697C>G		non_coding_transcript_exon_variant	Exon 4 of 4	4
JAG1	ENST00000617965.2	n.2889C>G		non_coding_transcript_exon_variant	Exon 12 of 17	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

JAG1-related disorder Uncertain:1

Jul 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The JAG1 c.2300C>G variant is predicted to result in the amino acid substitution p.Thr767Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.0032
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.93	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.60
Sift	Benign	0.33	T
Sift4G	Benign	0.29	T
Polyphen		0.089	B
Vest4		0.77
MutPred		0.62		Gain of catalytic residue at T767 (P = 0.0581);
MVP		0.94
MPC		0.62
ClinPred		0.76	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 0
DS_DL_spliceai		0.42		Position offset: -44

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: chr20-10625555;