rs1801138

Variant names:

• chr20-10658574-G-A
• rs1801138
• NM_000214.3:c.588C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10658574-G-A
• chr20-10658574-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.588C>T​(p.Cys196Cys) variant causes a synonymous change. The variant allele was found at a frequency of 0.0705 in 1,614,084 control chromosomes in the GnomAD database, including 7,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.11 (1516 hom., cov: 33)
  • Exomes 𝑓: 0.066 (6140 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.92
• Publications: 26 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 20-10658574-G-A is Benign according to our data. Variant chr20-10658574-G-A is described in ClinVar as Benign. ClinVar VariationId is 42481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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.588C>T	p.Cys196Cys	synonymous	Exon 4 of 26	NP_000205.1	P78504-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.588C>T	p.Cys196Cys	synonymous	Exon 4 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.588C>T	p.Cys196Cys	synonymous	Exon 5 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.588C>T	p.Cys196Cys	synonymous	Exon 4 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16720 AN: 152106 Hom.: 1487 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.106 AC: 26650 AN: 251446 AF XY: 0.106

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.0936

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.0215

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0891

GnomAD4 exome AF: 0.0664 AC: 97031 AN: 1461858 Hom.: 6140 Cov.: 34 AF XY: 0.0699 AC XY: 50834 AN XY: 727230

African (AFR) AF: 0.233 AC: 7809 AN: 33476

American (AMR) AF: 0.140 AC: 6252 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0936 AC: 2446 AN: 26136

East Asian (EAS) AF: 0.244 AC: 9688 AN: 39698

South Asian (SAS) AF: 0.209 AC: 17987 AN: 86256

European-Finnish (FIN) AF: 0.0224 AC: 1197 AN: 53420

Middle Eastern (MID) AF: 0.143 AC: 827 AN: 5768

European-Non Finnish (NFE) AF: 0.0409 AC: 45439 AN: 1111988

Other (OTH) AF: 0.0892 AC: 5386 AN: 60392

GnomAD4 genome AF: 0.110 AC: 16799 AN: 152226 Hom.: 1516 Cov.: 33 AF XY: 0.111 AC XY: 8281 AN XY: 74426

African (AFR) AF: 0.223 AC: 9267 AN: 41514

American (AMR) AF: 0.107 AC: 1638 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 330 AN: 3472

East Asian (EAS) AF: 0.220 AC: 1139 AN: 5166

South Asian (SAS) AF: 0.214 AC: 1034 AN: 4822

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10614

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0423 AC: 2877 AN: 68018

Other (OTH) AF: 0.101 AC: 213 AN: 2114

Alfa AF: 0.0732 Hom.: 2146

Bravo AF: 0.122

Asia WGS AF: 0.213 AC: 740 AN: 3478

EpiCase AF: 0.0537

EpiControl AF: 0.0533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	not provided (2)
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.91
PhyloP100		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801138; hg19: chr20-10639222; COSMIC: COSV54757520;