rs147229008

Variant names:

• chr20-10649067-G-A
• rs147229008
• NM_000214.3:c.1389C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000214.3(JAG1):​c.1389C>T​(p.Ser463Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,609,458 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.610
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 20-10649067-G-A is Benign according to our data. Variant chr20-10649067-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000512 (78/152226) while in subpopulation AMR AF = 0.00229 (35/15288). AF 95% confidence interval is 0.00169. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 78 AD gene.

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.1389C>T	p.Ser463Ser	synonymous	Exon 11 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.1389C>T	p.Ser463Ser	synonymous	Exon 11 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.1389C>T	p.Ser463Ser	synonymous	Exon 12 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.1389C>T	p.Ser463Ser	synonymous	Exon 11 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000465 AC: 117 AN: 251380 AF XY: 0.000500

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000425 AC: 620 AN: 1457232 Hom.: 1 Cov.: 29 AF XY: 0.000462 AC XY: 335 AN XY: 725396

African (AFR) AF: 0.0000899 AC: 3 AN: 33376

American (AMR) AF: 0.00134 AC: 60 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.000446 AC: 494 AN: 1107808

Other (OTH) AF: 0.000581 AC: 35 AN: 60210

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152226 Hom.: 1 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74364

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00229 AC: 35 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00633 AC: 2 AN: 316

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68038

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000529

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs147229008; hg19: chr20-10629715;