rs181970528

chr20-10650286-C-Achr20-10650286-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000214.3(JAG1):c.1195G>T(p.Val399Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V399M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, JAG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.3104292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.1195G>T	p.Val399Leu	missense_variant	9/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.1195G>T	p.Val399Leu	missense_variant	9/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.1061G>T		non_coding_transcript_exon_variant	7/25	2
JAG1	ENST00000617965.2	n.1784G>T		non_coding_transcript_exon_variant	3/17	5
JAG1	ENST00000622545.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251266 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.35	N
MutationTaster	Benign	0.57	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.19
Sift	Benign	0.87	T
Sift4G	Benign	0.38	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.49		Gain of catalytic residue at V399 (P = 0.0103);
MVP		0.58
MPC		0.45
ClinPred		0.16	T
GERP RS		3.7
Varity_R		0.070
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs181970528; hg19: chr20-10630934;