rs1135401949

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000214.3(JAG1):c.71T>C(p.Leu24Pro) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L24R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.50

Publications

0 publications found

Variant links:

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 links:

ENSG00000270792 (HGNC:):

ENSG00000270792 links:

LINC01752 (HGNC:52540): (long intergenic non-protein coding RNA 1752)

LINC01752 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 40 uncertain 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 chr20-10673460-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3573165.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3 link	c.71T>C	p.Leu24Pro	missense_variant	Exon 1 of 26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 link	c.71T>C	p.Leu24Pro	missense_variant	Exon 1 of 26	1	NM_000214.3	ENSP00000254958.4	P78504-1
ENSG00000270792	ENST00000605292.5 link	n.98+435A>G		intron_variant	Intron 1 of 4	3
LINC01752	ENST00000667822.1 link	n.331+435A>G		intron_variant	Intron 1 of 1
LINC01752	ENST00000716704.1 link	n.313+435A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.72e-7

AC:

AN:

1294682

Hom.:

Cov.:

AF XY:

0.00000158

AC XY:

AN XY:

633638

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25270

American (AMR)

AF:

0.00

AC:

AN:

19532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19750

East Asian (EAS)

AF:

0.00

AC:

AN:

30728

South Asian (SAS)

AF:

0.00

AC:

AN:

64426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3894

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1032570

Other (OTH)

AF:

0.0000189

AC:

AN:

52890

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation

Uncertain:1

Mar 08, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.62

Eigen

Benign

0.16

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.082

MutationAssessor

Benign

0.0

PhyloP100

1.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.2

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.69

MutPred

0.69

Gain of loop (P = 3e-04);

MVP

0.95

MPC

1.7

ClinPred

0.71

GERP RS

3.6

Varity_R

0.85

gMVP

0.47

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over