rs56225585

Variant names:

• chr20-10643854-G-A
• rs56225585
• NM_000214.3:c.2382C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-10643854-G-A
• chr20-10643854-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000214.3(JAG1):​c.2382C>T​(p.Ser794Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,512 control chromosomes in the GnomAD database, including 3,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1626 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1498 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.337
• Publications: 6 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=-0.48).
• BP6: Variant 20-10643854-G-A is Benign according to our data. Variant chr20-10643854-G-A is described in ClinVar as Benign. ClinVar VariationId is 42474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.337 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 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.2382C>T	p.Ser794Ser	synonymous	Exon 20 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.2382C>T	p.Ser794Ser	synonymous	Exon 20 of 26	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.2382C>T	p.Ser794Ser	synonymous	Exon 21 of 27	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.2382C>T	p.Ser794Ser	synonymous	Exon 20 of 26	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 12479 AN: 151956 Hom.: 1622 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0391

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0230 AC: 5763 AN: 251072 AF XY: 0.0169

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00218

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.00949 AC: 13875 AN: 1461438 Hom.: 1498 Cov.: 31 AF XY: 0.00828 AC XY: 6022 AN XY: 727004

African (AFR) AF: 0.287 AC: 9592 AN: 33418

American (AMR) AF: 0.0183 AC: 818 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00121 AC: 104 AN: 86190

European-Finnish (FIN) AF: 0.00165 AC: 88 AN: 53404

Middle Eastern (MID) AF: 0.0193 AC: 111 AN: 5766

European-Non Finnish (NFE) AF: 0.00166 AC: 1850 AN: 1111754

Other (OTH) AF: 0.0213 AC: 1283 AN: 60376

GnomAD4 genome AF: 0.0822 AC: 12504 AN: 152074 Hom.: 1626 Cov.: 32 AF XY: 0.0796 AC XY: 5922 AN XY: 74354

African (AFR) AF: 0.280 AC: 11585 AN: 41400

American (AMR) AF: 0.0390 AC: 597 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10602

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68006

Other (OTH) AF: 0.0695 AC: 147 AN: 2114

Alfa AF: 0.0327 Hom.: 437

Bravo AF: 0.0937

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Alagille syndrome due to a JAG1 point mutation (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Isolated Nonsyndromic Congenital Heart Disease (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.74
PhyloP100		-0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs56225585; hg19: chr20-10624502;