rs79338570

chr20-10672794-G-Achr20-10672794-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000214.3(JAG1):c.294C>T(p.Ser98=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,114 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S98S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (41 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.610

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 20-10672794-G-A is Benign according to our data. Variant chr20-10672794-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10672794-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2034/152304) while in subpopulation AFR AF= 0.0471 (1958/41578). AF 95% confidence interval is 0.0454. There are 44 homozygotes in gnomad4. There are 953 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2031 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.294C>T	p.Ser98=	synonymous_variant	2/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.294C>T	p.Ser98=	synonymous_variant	2/26	1	NM_000214.3	P1
	ENST00000667822.1	n.100G>A		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2031 AN: 152188 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00343 AC: 857 AN: 250094 Hom.: 17 AF XY: 0.00243 AC XY: 330 AN XY: 135690

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000698

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00141 AC: 2065 AN: 1460810 Hom.: 41 Cov.: 33 AF XY: 0.00118 AC XY: 860 AN XY: 726738

Gnomad4 AFR exome AF: 0.0489

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.0134 AC: 2034 AN: 152304 Hom.: 44 Cov.: 33 AF XY: 0.0128 AC XY: 953 AN XY: 74472

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00435 Hom.: 3

Bravo AF: 0.0146

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2017	- -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2016

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
BayesDel_noAF	Benign	-0.60
Cadd	Benign	9.6
Dann	Benign	0.95

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

Other links and lift over

dbSNP: rs79338570; hg19: chr20-10653442;