rs368734792

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP6_ModerateBS2

The NM_000214.3(JAG1):​c.2728G>A​(p.Glu910Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

1
7
11

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.
BP6
Variant 20-10641648-C-T is Benign according to our data. Variant chr20-10641648-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 536529.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-10641648-C-T is described in Lovd as [Likely_benign].
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
JAG1NM_000214.3 linkc.2728G>A p.Glu910Lys missense_variant Exon 23 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.2728G>A p.Glu910Lys missense_variant Exon 23 of 26 1 NM_000214.3 ENSP00000254958.4 P78504-1
JAG1ENST00000423891.6 linkn.2594G>A non_coding_transcript_exon_variant Exon 21 of 25 2
JAG1ENST00000617965.2 linkn.3317G>A non_coding_transcript_exon_variant Exon 17 of 17 5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250860
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135656
show subpopulations
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:
0.0000653
Gnomad FIN exome
AF:
0.0000467
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461592
Hom.:
0
Cov.:
33
AF XY:
0.00000963
AC XY:
7
AN XY:
727140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152212
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Alagille syndrome due to a JAG1 point mutation Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 27, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
0.15
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Benign
0.042
D
MetaRNN
Uncertain
0.55
D
MetaSVM
Benign
-0.32
T
MutationAssessor
Benign
1.3
L
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.93
N
REVEL
Uncertain
0.33
Sift
Benign
0.42
T
Sift4G
Benign
0.55
T
Polyphen
0.47
P
Vest4
0.63
MVP
0.58
MPC
0.57
ClinPred
0.37
T
GERP RS
5.7
Varity_R
0.10
gMVP
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368734792; hg19: chr20-10622296; COSMIC: COSV54758216; COSMIC: COSV54758216; API