rs143966918

chr20-10639688-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BS1_Supporting BS2

The NM_000214.3(JAG1):c.3467T>C(p.Val1156Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: JAG1 NM_000214.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.35

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, JAG1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17765579).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000131 (20/152162) while in subpopulation NFE AF= 0.000265 (18/68028). AF 95% confidence interval is 0.000171. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAG1	NM_000214.3	c.3467T>C	p.Val1156Ala	missense_variant	26/26	ENST00000254958.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAG1	ENST00000254958.10	c.3467T>C	p.Val1156Ala	missense_variant	26/26	1	NM_000214.3	P1
JAG1	ENST00000423891.6	n.3333T>C		non_coding_transcript_exon_variant	24/25	2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251478 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135916

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.000140 AC XY: 102 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74346

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000948 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2017	The V1156A variant in the JAG1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1156A variant is observed in 1/6614 (0.015%) alleles from individuals of Finnish background in the ExAC dataset (Lek et al., 2016). The V1156A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V1156A as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2017	- -

Tetralogy of Fallot;C1866053:Deafness, congenital heart defects, and posterior embryotoxon;C1956125:Alagille syndrome due to a JAG1 point mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Alagille syndrome due to a JAG1 point mutation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Benign	0.91
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.10	N
REVEL	Uncertain	0.39
Sift	Benign	0.88	T
Sift4G	Benign	0.58	T
Polyphen		0.10	B
Vest4		0.37
MVP		0.62
MPC		0.56
ClinPred		0.086	T
GERP RS		5.5
Varity_R		0.076
gMVP		0.19

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: rs143966918; hg19: chr20-10620336;