rs200816814
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP3BP6
The NM_017617.5(NOTCH1):c.2218G>T(p.Asp740Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict 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. D740N) has been classified as Uncertain significance.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2218G>T | p.Asp740Tyr | missense_variant | 14/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.507+3548C>A | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.1495G>T | p.Asp499Tyr | missense_variant | 11/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.2218G>T | p.Asp740Tyr | missense_variant | 14/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247828Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135032
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460698Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726638
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 09, 2022 | The p.D740Y variant (also known as c.2218G>T), located in coding exon 14 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 2218. The aspartic acid at codon 740 is replaced by tyrosine, an amino acid with highly dissimilar 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. - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at