chr20-10642618-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000214.3(JAG1):c.2459-17A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00832 in 1,476,638 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 53 hom. )

Consequence

JAG1
NM_000214.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.489

Publications

1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
Charcot-Marie-Tooth disease, axonal, Type 2HH
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

JAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 20-10642618-T-G is Benign according to our data. Variant chr20-10642618-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00619 (942/152282) while in subpopulation AMR AF = 0.01 (153/15304). AF 95% confidence interval is 0.0088. There are 7 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 942 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.2459-17A>C		intron	N/A	NP_000205.1	P78504-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
JAG1	ENST00000254958.10	TSL:1 MANE Select	c.2459-17A>C	intron	N/A	ENSP00000254958.4	P78504-1
JAG1	ENST00000901230.1		c.2459-17A>C	intron	N/A	ENSP00000571289.1
JAG1	ENST00000913738.1		c.2459-17A>C	intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes

AF:

0.00619

AC:

942

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00941

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00687

AC:

1724

AN:

250870

AF XY:

0.00707

show subpopulations

Gnomad AFR exome

AF:

0.00216

Gnomad AMR exome

AF:

0.00524

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.0100

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00856

AC:

11343

AN:

1324356

Hom.:

Cov.:

AF XY:

0.00835

AC XY:

5563

AN XY:

666242

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

30794

American (AMR)

AF:

0.00563

AC:

251

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.000949

AC:

AN:

25298

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39028

South Asian (SAS)

AF:

0.0101

AC:

839

AN:

83482

European-Finnish (FIN)

AF:

0.00184

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00969

AC:

9563

AN:

986704

Other (OTH)

AF:

0.00834

AC:

464

AN:

55636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

525

1050

1576

2101

2626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00619

AC:

942

AN:

152282

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

438

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41560

American (AMR)

AF:

0.0100

AC:

153

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00643

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00941

AC:

640

AN:

68032

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00649

Hom.:

Bravo

AF:

0.00648

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Alagille syndrome due to a JAG1 point mutation (1)

Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation;C5562003:Charcot-Marie-Tooth disease, axonal, Type 2HH (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over