rs148990028

Positions:

chr20-10652540-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 5P and 11B. PM1PM5PP2BP4_ModerateBP6BS1BS2

The NM_000214.3(JAG1):c.814G>A(p.Val272Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V272F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

JAG1
NM_000214.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.91

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:

JAG1 (HGNC:):

JAG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a domain EGF-like 2; atypical (size 30) in uniprot entity JAG1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000214.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-10652540-C-A is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), JAG1. . Gene score misZ 3.2459 (greater than the threshold 3.09). Trascript score misZ 5.2848 (greater than threshold 3.09). GenCC has associacion of gene with tetralogy of fallot, Alagille syndrome due to a JAG1 point mutation, Charcot-Marie-Tooth disease, axonal, Type 2HH.

BP4

Computational evidence support a benign effect (MetaRNN=0.16709363).

BP6

Variant 20-10652540-C-T is Benign according to our data. Variant chr20-10652540-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 264345.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000394 (60/152246) while in subpopulation AFR AF= 0.00125 (52/41556). AF 95% confidence interval is 0.00098. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAG1	NM_000214.3 linkuse as main transcript	c.814G>A	p.Val272Ile	missense_variant	6/26	ENST00000254958.10	NP_000205.1	P78504-1Q99740

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JAG1	ENST00000254958.10 linkuse as main transcript	c.814G>A	p.Val272Ile	missense_variant	6/26	1	NM_000214.3	ENSP00000254958.4	P78504-1
JAG1	ENST00000423891.6 linkuse as main transcript	n.680G>A		non_coding_transcript_exon_variant	4/25	2
JAG1	ENST00000617965.2 linkuse as main transcript	n.183G>A		non_coding_transcript_exon_variant	1/17	5

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251392

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461422

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000394

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.000476

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2018	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2015

The p.V272I variant (also known as c.814G>A), located in coding exon 6 of the JAG1 gene, results from a G to A substitution at nucleotide position 814. The valine at codon 272 is replaced by isoleucine, an amino acid with highly similar properties. Another alteration affecting the same amino acid, p.V272F (c.814G>T), has been previously reported in association with tetralogy of Fallot (Kola S et al. Clin Chim Acta. 2011;412(23-24):2232-6). The p.V272I variant was previously reported in the SNPDatabase as rs148990028. Based on data from ExAC, the A allele has an overall frequency of approximately 0.01% (23/121252). The highest observed frequency was approximately 0.1% (11/10390) of African alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed October 12, 2015]). Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.03% (4/13006) total alleles studied, having been observed in 0.09% (4/4406) African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Alagille syndrome due to a JAG1 point mutation

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

- -

JAG1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.073

MetaRNN

Benign

0.17

MetaSVM

Uncertain

-0.091

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.73

REVEL

Uncertain

0.43

Sift

Benign

0.11

Sift4G

Benign

0.18

Polyphen

0.92

Vest4

0.57

MVP

0.69

MPC

2.1

ClinPred

0.060

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.45

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over