NM_000214.3:c.744A>G

Variant names:

• chr20-10656409-T-C
• rs10485741
• NM_000214.3:c.744A>G

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.744A>G​(p.Pro248Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 1,613,022 control chromosomes in the GnomAD database, including 4,713 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. P248P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.068 (393 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4320 hom.)
• Consequence: JAG1 NM_000214.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.927
• Publications: 20 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• Charcot-Marie-Tooth disease, axonal, Type 2HH

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.53).
• BP6: Variant 20-10656409-T-C is Benign according to our data. Variant chr20-10656409-T-C is described in ClinVar as Benign. ClinVar VariationId is 42482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.927 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0892 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.744A>G	p.Pro248Pro	synonymous	Exon 5 of 26	NP_000205.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	ENST00000254958.10	TSL:1 MANE Select	c.744A>G	p.Pro248Pro	synonymous	Exon 5 of 26	ENSP00000254958.4
	JAG1	ENST00000423891.6	TSL:2	n.610A>G		non_coding_transcript_exon	Exon 3 of 25

Frequencies

GnomAD3 genomes AF: 0.0683 AC: 10392 AN: 152218 Hom.: 393 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0929

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0503

Gnomad FIN AF: 0.0796

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0770

Gnomad OTH AF: 0.0579

GnomAD2 exomes AF: 0.0723 AC: 18171 AN: 251246 AF XY: 0.0694

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0837

Gnomad NFE exome AF: 0.0759

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0732 AC: 106913 AN: 1460686 Hom.: 4320 Cov.: 30 AF XY: 0.0720 AC XY: 52343 AN XY: 726724

African (AFR) AF: 0.0585 AC: 1959 AN: 33466

American (AMR) AF: 0.121 AC: 5424 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 304 AN: 26120

East Asian (EAS) AF: 0.0196 AC: 779 AN: 39692

South Asian (SAS) AF: 0.0582 AC: 5015 AN: 86234

European-Finnish (FIN) AF: 0.0872 AC: 4651 AN: 53366

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5764

European-Non Finnish (NFE) AF: 0.0764 AC: 84873 AN: 1110972

Other (OTH) AF: 0.0629 AC: 3795 AN: 60360

GnomAD4 genome AF: 0.0683 AC: 10403 AN: 152336 Hom.: 393 Cov.: 32 AF XY: 0.0679 AC XY: 5059 AN XY: 74490

African (AFR) AF: 0.0565 AC: 2351 AN: 41578

American (AMR) AF: 0.0932 AC: 1427 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5188

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4828

European-Finnish (FIN) AF: 0.0796 AC: 845 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0770 AC: 5235 AN: 68028

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

Alfa AF: 0.0665 Hom.: 747

Bravo AF: 0.0681

Asia WGS AF: 0.0420 AC: 145 AN: 3478

EpiCase AF: 0.0671

EpiControl AF: 0.0648

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.99
DANN	Benign	0.75
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs10485741; hg19: chr20-10637057; COSMIC: COSV54757219; COSMIC: COSV54757219;