20-10648679-G-A
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2
The NM_000214.3(JAG1):c.1439C>T(p.Ala480Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,614,202 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A480S) has been classified as Likely benign.
Frequency
Consequence
NM_000214.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JAG1 | NM_000214.3 | c.1439C>T | p.Ala480Val | missense_variant | 12/26 | ENST00000254958.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JAG1 | ENST00000254958.10 | c.1439C>T | p.Ala480Val | missense_variant | 12/26 | 1 | NM_000214.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00132 AC: 333AN: 251440Hom.: 7 AF XY: 0.00183 AC XY: 249AN XY: 135894
GnomAD4 exome AF: 0.000613 AC: 896AN: 1461856Hom.: 12 Cov.: 33 AF XY: 0.000916 AC XY: 666AN XY: 727224
GnomAD4 genome AF: 0.000236 AC: 36AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31AN XY: 74504
ClinVar
Submissions by phenotype
Alagille syndrome due to a JAG1 point mutation Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2021 | The p.A480V variant (also known as c.1439C>T), located in coding exon 12 of the JAG1 gene, results from a C to T substitution at nucleotide position 1439. The alanine at codon 480 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Isolated Nonsyndromic Congenital Heart Disease Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at