20-10637926-T-C

Variant names:

• chr20-10637926-T-C
• rs8708
• NM_000214.3:c.*1572A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000214.3(JAG1):​c.*1572A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,542 control chromosomes in the GnomAD database, including 23,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23632 hom., cov: 33)
  • Exomes 𝑓: 0.56 (64 hom.)
• Consequence: JAG1 NM_000214.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.16

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 20-10637926-T-C is Benign according to our data. Variant chr20-10637926-T-C is described in ClinVar as [Benign]. Clinvar id is 337715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JAG1	NM_000214.3	c.*1572A>G		3_prime_UTR_variant	Exon 26 of 26	ENST00000254958.10	NP_000205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JAG1	ENST00000254958	c.*1572A>G		3_prime_UTR_variant	Exon 26 of 26	1	NM_000214.3	ENSP00000254958.4
JAG1	ENST00000423891.6	n.3591A>G		non_coding_transcript_exon_variant	Exon 25 of 25	2

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83738 AN: 152006 Hom.: 23597 Cov.: 33

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.551

GnomAD4 exome AF: 0.557 AC: 233 AN: 418 Hom.: 64 Cov.: 0 AF XY: 0.528 AC XY: 132 AN XY: 250

Gnomad4 FIN exome AF: 0.561

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.551 AC: 83829 AN: 152124 Hom.: 23632 Cov.: 33 AF XY: 0.547 AC XY: 40692 AN XY: 74344

Gnomad4 AFR AF: 0.535

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.545

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.553

Alfa AF: 0.569 Hom.: 33039

Bravo AF: 0.545

Asia WGS AF: 0.392 AC: 1365 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 28, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22336710) -

Isolated Nonsyndromic Congenital Heart Disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.22
DANN	Benign	0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs8708; hg19: chr20-10618574; COSMIC: COSV54756127; COSMIC: COSV54756127;