20-10639572-T-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000214.3(JAG1):​c.3583A>G​(p.Asn1195Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

6
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.99

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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.25765678).
BP6
Variant 20-10639572-T-C is Benign according to our data. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479. Variant chr20-10639572-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 42479.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000526 (8/152152) while in subpopulation AFR AF = 0.000193 (8/41418). AF 95% confidence interval is 0.0000957. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAG1NM_000214.3 linkc.3583A>G p.Asn1195Asp missense_variant Exon 26 of 26 ENST00000254958.10 NP_000205.1 P78504-1Q99740

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
JAG1ENST00000254958.10 linkc.3583A>G p.Asn1195Asp missense_variant Exon 26 of 26 1 NM_000214.3 ENSP00000254958.4 P78504-1
JAG1ENST00000423891.6 linkn.3449A>G non_coding_transcript_exon_variant Exon 24 of 25 2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251448
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461870
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727234
show subpopulations
African (AFR)
AF:
0.0000597
AC:
2
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112004
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
AF:
0.0000526
AC:
8
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74326
show subpopulations
African (AFR)
AF:
0.000193
AC:
8
AN:
41418
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 10, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The Asn1195Asp variant in JAG1 has not been reported in the literature. It has been detected by our laboratory in one individual of Black ancestry with suspect ed Alagille syndrome. This individual carried another, pathogenic varant in the JAG1 gene, making it difficult to predict the effect of the Asn1195Asp variant in isolation. Asparagine (Asn) at position 1195 is conserved evolutionarily dis tant species, indicating that a change may not be tolerated. However, it should be noted that this lab has sequenced the JAG1 gene in only a small number of Bla ck individuals and no Black healthy controls. In addition, healthy control infor mation is unavailable from either public databases or scientific literature, suc h that the full spectrum of benign variation has not yet been defined for this p opulation. Future analysis could therefore reveal that the Asn1195Asp variant is common unlikely to be pathogenic. In summary, the clinical significance of this variant cannot be determined at this time due to occurrence with another, patho genic variant as well as lack of control data. -

Cardiovascular phenotype Uncertain:1
Jun 22, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3583A>G (p.N1195D) alteration is located in exon 26 (coding exon 26) of the JAG1 gene. This alteration results from a A to G substitution at nucleotide position 3583, causing the asparagine (N) at amino acid position 1195 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Alagille syndrome due to a JAG1 point mutation Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D
Eigen
Benign
-0.059
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.26
T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.9
L
PhyloP100
5.0
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.30
Sift
Benign
0.14
T
Sift4G
Benign
0.61
T
Polyphen
0.049
B
Vest4
0.37
MutPred
0.077
Gain of phosphorylation at T1197 (P = 0.1003);
MVP
0.83
MPC
0.57
ClinPred
0.31
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.25
gMVP
0.090
Mutation Taster
=74/26
polymorphism

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

Other links and lift over

dbSNP: rs397515876; hg19: chr20-10620220; API