9-136505818-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_017617.5(NOTCH1):c.4078G>A(p.Gly1360Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000327 in 1,592,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000451 AC: 1AN: 221908Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 123526
GnomAD4 exome AF: 0.0000333 AC: 48AN: 1439834Hom.: 0 Cov.: 33 AF XY: 0.0000294 AC XY: 21AN XY: 715486
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:4
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NOTCH1: PP2 -
Adams-Oliver syndrome 5 Uncertain:1Benign:1
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NOTCH1-related disorder Uncertain:1
The NOTCH1 c.4078G>A variant is predicted to result in the amino acid substitution p.Gly1360Ser. This variant has been reported in a patient with a congenital heart defect (Blue et al 2014. PubMed ID: 25500235). This variant is reported in 0.0090% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.G1360S variant (also known as c.4078G>A), located in coding exon 25 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 4078. The glycine at codon 1360 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5298 samples (10596 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Aortic valve disease 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at