rs200311847

Positions:

• chr20-10652449-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000214.3(JAG1):​c.886+19A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,613,604 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: JAG1 NM_000214.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.240

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=-0.81).
• BP6: Variant 20-10652449-T-A is Benign according to our data. Variant chr20-10652449-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 255562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-10652449-T-A is described in Lovd as [Benign]. Variant chr20-10652449-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00216 (329/152250) while in subpopulation NFE AF= 0.00398 (271/68006). AF 95% confidence interval is 0.00359. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 329 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.886+19A>T		intron_variant		ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.886+19A>T		intron_variant		1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.752+19A>T		intron_variant, non_coding_transcript_variant		2
JAG1	ENST00000617965.2	n.255+19A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 329 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00213 AC: 535 AN: 251304 Hom.: 2 AF XY: 0.00226 AC XY: 307 AN XY: 135852

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00370

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00276 AC: 4027 AN: 1461354 Hom.: 7 Cov.: 33 AF XY: 0.00265 AC XY: 1925 AN XY: 726980

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00334

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152250 Hom.: 1 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74460

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00316 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Alagille syndrome due to a JAG1 point mutation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.29
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs200311847; hg19: chr20-10633097;