rs1051415

Variant names:

• chr20-10672821-C-T
• rs1051415
• NM_000214.3:c.267G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.267G>A​(p.Gly89Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,164 control chromosomes in the GnomAD database, including 10,148 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 (i.e. G89G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.082 (672 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9476 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.106
• Publications: 18 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]

LINC01752 (HGNC:52540): (long intergenic non-protein coding RNA 1752)

ENSG00000270792 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 20-10672821-C-T is Benign according to our data. Variant chr20-10672821-C-T is described in ClinVar as Benign. ClinVar VariationId is 42476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.106 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 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.267G>A	p.Gly89Gly	synonymous	Exon 2 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.267G>A	p.Gly89Gly	synonymous	Exon 2 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.267G>A	p.Gly89Gly	synonymous	Exon 3 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.267G>A	p.Gly89Gly	synonymous	Exon 2 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12504 AN: 152158 Hom.: 671 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0956

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.0702

GnomAD2 exomes AF: 0.0960 AC: 24042 AN: 250386 AF XY: 0.0924

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.113

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.0899

GnomAD4 exome AF: 0.108 AC: 157413 AN: 1460888 Hom.: 9476 Cov.: 35 AF XY: 0.105 AC XY: 76068 AN XY: 726764

African (AFR) AF: 0.0163 AC: 546 AN: 33478

American (AMR) AF: 0.119 AC: 5319 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 923 AN: 26134

East Asian (EAS) AF: 0.0753 AC: 2989 AN: 39700

South Asian (SAS) AF: 0.0420 AC: 3624 AN: 86258

European-Finnish (FIN) AF: 0.121 AC: 6358 AN: 52446

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 131847 AN: 1111998

Other (OTH) AF: 0.0940 AC: 5674 AN: 60384

GnomAD4 genome AF: 0.0822 AC: 12513 AN: 152276 Hom.: 672 Cov.: 33 AF XY: 0.0807 AC XY: 6010 AN XY: 74444

African (AFR) AF: 0.0213 AC: 886 AN: 41566

American (AMR) AF: 0.0960 AC: 1469 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.111 AC: 574 AN: 5156

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4832

European-Finnish (FIN) AF: 0.114 AC: 1204 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7853 AN: 68020

Other (OTH) AF: 0.0690 AC: 146 AN: 2116

Alfa AF: 0.0964 Hom.: 416

Bravo AF: 0.0794

Asia WGS AF: 0.0660 AC: 228 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.0995

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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)
-	-	1	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		0.11
Mutation Taster		=90/10	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: rs1051415; hg19: chr20-10653469; COSMIC: COSV54757776; COSMIC: COSV54757776;