chr20-10652212-C-A

Variant names:

• chr20-10652212-C-A
• rs750195672
• NM_000214.3:c.925G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000214.3(JAG1):​c.925G>T​(p.Gly309Trp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G309R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21
• Publications: 0 publications found

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]

JAG1 Gene-Disease associations (from GenCC):

• Alagille syndrome due to a JAG1 point mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• tetralogy of fallot

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.925G>T	p.Gly309Trp	missense	Exon 7 of 26	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.925G>T	p.Gly309Trp	missense	Exon 7 of 26	ENSP00000254958.4
	JAG1	ENST00000423891.6	TSL:2	n.791G>T		non_coding_transcript_exon	Exon 5 of 25
	JAG1	ENST00000617965.2	TSL:5	n.294G>T		non_coding_transcript_exon	Exon 2 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Uncertain:1

Jun 23, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		4.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.81		Loss of disorder (P = 0.0034)
MVP		0.97
MPC		2.5
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.81
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs750195672; hg19: chr20-10632860;