rs147809756

Positions:

• chr20-10644976-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP6_Very_Strong BS1 BS2

The NM_000214.3(JAG1):​c.2231G>A​(p.Arg744Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,612,916 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:8
• Conservation: PhyloP100: 4.76

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, JAG1
• BP6: Variant 20-10644976-C-T is Benign according to our data. Variant chr20-10644976-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 337752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10644976-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000706 (107/151572) while in subpopulation SAS AF= 0.00146 (7/4790). AF 95% confidence interval is 0.000904. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.2231G>A	p.Arg744Gln	missense_variant	18/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.2231G>A	p.Arg744Gln	missense_variant	18/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.2097G>A		non_coding_transcript_exon_variant	16/25	2
JAG1	ENST00000488480.2	n.628G>A		non_coding_transcript_exon_variant	4/4	4
JAG1	ENST00000617965.2	n.2820G>A		non_coding_transcript_exon_variant	12/17	5

Frequencies

GnomAD3 genomes AF: 0.000706 AC: 107 AN: 151454 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000946 AC: 238 AN: 251478 Hom.: 0 AF XY: 0.00116 AC XY: 157 AN XY: 135912

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00140

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00105 AC: 1529 AN: 1461344 Hom.: 3 Cov.: 31 AF XY: 0.00112 AC XY: 811 AN XY: 727036

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000706 AC: 107 AN: 151572 Hom.: 0 Cov.: 33 AF XY: 0.000567 AC XY: 42 AN XY: 74072

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000918

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00111

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000793

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	JAG1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	This variant is associated with the following publications: (PMID: 11139239, 10220506, 11157803, 11058898, 26760175) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 13, 2017

- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

JAG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2018

This alteration is classified as likely 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	0.079
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.041	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.029	D
Sift4G	Benign	0.16	T
Polyphen		0.57	P
Vest4		0.48
MVP		0.76
MPC		0.59
ClinPred		0.027	T
GERP RS		6.1
Varity_R		0.17
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147809756; hg19: chr20-10625624; COSMIC: COSV54753280; COSMIC: COSV54753280;