rs112196689

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000214.3(JAG1):​c.2573-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,524,598 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0056 ( 11 hom., cov: 33)
Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

JAG1
NM_000214.3 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.99
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 20-10641908-G-A is Benign according to our data. Variant chr20-10641908-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10641908-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00563 (858/152282) while in subpopulation AFR AF= 0.0199 (827/41570). AF 95% confidence interval is 0.0188. There are 11 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 858 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JAG1NM_000214.3 linkc.2573-16C>T intron_variant ENST00000254958.10 NP_000205.1 P78504-1Q99740

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JAG1ENST00000254958.10 linkc.2573-16C>T intron_variant 1 NM_000214.3 ENSP00000254958.4 P78504-1
JAG1ENST00000423891.6 linkn.2439-16C>T intron_variant 2
JAG1ENST00000617965.2 linkn.3162-16C>T intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00563
AC:
857
AN:
152168
Hom.:
11
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0199
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
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:
0.0000588
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00153
AC:
385
AN:
250962
Hom.:
1
AF XY:
0.00111
AC XY:
151
AN XY:
135646
show subpopulations
Gnomad AFR exome
AF:
0.0224
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000585
AC:
803
AN:
1372316
Hom.:
3
Cov.:
23
AF XY:
0.000491
AC XY:
338
AN XY:
687960
show subpopulations
Gnomad4 AFR exome
AF:
0.0210
Gnomad4 AMR exome
AF:
0.000628
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000237
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.00106
GnomAD4 genome
AF:
0.00563
AC:
858
AN:
152282
Hom.:
11
Cov.:
33
AF XY:
0.00520
AC XY:
387
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0199
Gnomad4 AMR
AF:
0.00111
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00266
Hom.:
1
Bravo
AF:
0.00642

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 17, 2024- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Alagille syndrome due to a JAG1 point mutation Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.026
DANN
Benign
0.77

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: rs112196689; hg19: chr20-10622556; API