NM_017617.5:c.6727G>A
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_017617.5(NOTCH1):c.6727G>A(p.Gly2243Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,609,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G2243G) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
Publications
- Adams-Oliver syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
- Adams-Oliver syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- aortic valve disease 1Inheritance: AD Classification: STRONG Submitted by: G2P, PanelApp Australia
- connective tissue disorderInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- leukodystrophyInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- familial bicuspid aortic valveInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152214Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000287 AC: 7AN: 243582 AF XY: 0.0000300 show subpopulations
GnomAD4 exome AF: 0.0000343 AC: 50AN: 1457606Hom.: 0 Cov.: 32 AF XY: 0.0000345 AC XY: 25AN XY: 724870 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74366 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
BP4 -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.G2243S variant (also known as c.6727G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6727. The glycine at codon 2243 is replaced by serine, an amino acid with similar properties. This variant was detected in a pediatric patient with T-cell acute lymphoblastic leukemia where NOTCH1 was only partially sequenced and clinical information was not available (Kraszewska MD et al, Blood Cells Mol. Dis. 2013 Jan; 50(1):33-8). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Adams-Oliver syndrome 5 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at