rs6040050

Variant names:

• chr20-10640565-C-T
• rs6040050
• NM_000214.3:c.3199+218G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000214.3(JAG1):​c.3199+218G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,082 control chromosomes in the GnomAD database, including 5,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (5251 hom., cov: 33)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.163
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-10640565-C-T is Benign according to our data. Variant chr20-10640565-C-T is described in ClinVar as Benign. ClinVar VariationId is 1296329.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.362 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.3199+218G>A		intron	N/A	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.3199+218G>A		intron	N/A	ENSP00000254958.4	P78504-1
	JAG1	ENST00000901230.1		c.3199+218G>A		intron	N/A	ENSP00000571289.1
	JAG1	ENST00000913738.1		c.3193+218G>A		intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37529 AN: 151964 Hom.: 5249 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.281

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.247 AC: 37561 AN: 152082 Hom.: 5251 Cov.: 33 AF XY: 0.247 AC XY: 18324 AN XY: 74336

African (AFR) AF: 0.128 AC: 5295 AN: 41508

American (AMR) AF: 0.370 AC: 5648 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1033 AN: 3468

East Asian (EAS) AF: 0.160 AC: 824 AN: 5164

South Asian (SAS) AF: 0.206 AC: 990 AN: 4816

European-Finnish (FIN) AF: 0.250 AC: 2638 AN: 10558

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20024 AN: 67972

Other (OTH) AF: 0.282 AC: 596 AN: 2112

Alfa AF: 0.270 Hom.: 2236

Bravo AF: 0.249

Asia WGS AF: 0.195 AC: 677 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.46
PhyloP100		-0.16
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: rs6040050; hg19: chr20-10621213;