20-10652533-C-T

Variant names:

• chr20-10652533-C-T
• rs28939668
• NM_000214.3:c.821G>A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000214.3(JAG1):​c.821G>A​(p.Gly274Asp) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G274R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 13 ACMG points.

• PM1: In a domain EGF-like 2; atypical (size 30) in uniprot entity JAG1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr20-10652534-C-G is described in Lovd as [Likely_pathogenic].
• 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, 0.992
• PP5: Variant 20-10652533-C-T is Pathogenic according to our data. Variant chr20-10652533-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7624.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-10652533-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.821G>A	p.Gly274Asp	missense_variant	Exon 6 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958.10	c.821G>A	p.Gly274Asp	missense_variant	Exon 6 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.687G>A		non_coding_transcript_exon_variant	Exon 4 of 25	2
JAG1	ENST00000617965.2	n.190G>A		non_coding_transcript_exon_variant	Exon 1 of 17	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Pathogenic:1

Apr 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change has a deleterious effect on several aspects of JAG1 protein function including structural stability, localization and ability to activate NOTCH signaling  (PMID: 19780835, 12649809). This sequence change replaces glycine with aspartic acid at codon 274 of the JAG1 protein (p.Gly274Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with tetralogy of Fallot in a large family (PMID:11152664).  ClinVar contains an entry for this variant (Variation ID: 7624). In summary this is a rare missense change which has been shown to segregate with disease in one family and affects protein function, for these reasons it has been classified as Likely Pathogenic. -

Tetralogy of Fallot Pathogenic:1

Apr 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.91		Loss of catalytic residue at C276 (P = 0.0525);
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs28939668; hg19: chr20-10633181;