rs35761929

chr20-10641853-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):c.2612C>G(p.Pro871Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0657 in 1,613,100 control chromosomes in the GnomAD database, including 4,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (252 hom., cov: 33)
  • Exomes 𝑓: 0.067 (3997 hom.)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, JAG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.001998365).
• BP6: Variant 20-10641853-G-C is Benign according to our data. Variant chr20-10641853-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 42475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10641853-G-C is described in Lovd as [Likely_benign]. Variant chr20-10641853-G-C is described in Lovd as [Benign]. Variant chr20-10641853-G-C is described in Lovd as [Likely_pathogenic]. Variant chr20-10641853-G-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.2612C>G	p.Pro871Arg	missense_variant	22/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.2612C>G	p.Pro871Arg	missense_variant	22/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.2478C>G		non_coding_transcript_exon_variant	20/25	2
JAG1	ENST00000617965.2	n.3201C>G		non_coding_transcript_exon_variant	16/17	5

Frequencies

GnomAD3 genomes AF: 0.0508 AC: 7726 AN: 152166 Hom.: 255 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0294

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0692

Gnomad OTH AF: 0.0449

GnomAD3 exomes AF: 0.0634 AC: 15942 AN: 251368 Hom.: 746 AF XY: 0.0693 AC XY: 9418 AN XY: 135848

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.0329

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.0814

Gnomad NFE exome AF: 0.0669

Gnomad OTH exome AF: 0.0595

GnomAD4 exome AF: 0.0673 AC: 98286 AN: 1460816 Hom.: 3997 Cov.: 32 AF XY: 0.0694 AC XY: 50428 AN XY: 726824

Gnomad4 AFR exome AF: 0.0114

Gnomad4 AMR exome AF: 0.0203

Gnomad4 ASJ exome AF: 0.0203

Gnomad4 EAS exome AF: 0.0280

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0847

Gnomad4 NFE exome AF: 0.0673

Gnomad4 OTH exome AF: 0.0590

GnomAD4 genome AF: 0.0508 AC: 7732 AN: 152284 Hom.: 252 Cov.: 33 AF XY: 0.0515 AC XY: 3832 AN XY: 74458

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0335

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.0823

Gnomad4 NFE AF: 0.0692

Gnomad4 OTH AF: 0.0487

Alfa AF: 0.0584 Hom.: 82

Bravo AF: 0.0421

TwinsUK AF: 0.0663 AC: 246

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.0653 AC: 562

ExAC AF: 0.0662 AC: 8031

Asia WGS AF: 0.100 AC: 348 AN: 3478

EpiCase AF: 0.0646

EpiControl AF: 0.0605

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 03, 2010	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	D
Polyphen		0.99	D
Vest4		0.26
MPC		0.63
ClinPred		0.034	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs35761929; hg19: chr20-10622501; COSMIC: COSV54759656; COSMIC: COSV54759656;