rs138504021
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_017617.5(NOTCH1):c.1862G>T(p.Arg621Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,611,810 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621H) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.1862G>T | p.Arg621Leu | missense_variant | 11/34 | ENST00000651671.1 | NP_060087.3 | |
LOC124902310 | XR_007061865.1 | n.507+5545C>A | intron_variant, non_coding_transcript_variant | |||||
NOTCH1 | XM_011518717.3 | c.1139G>T | p.Arg380Leu | missense_variant | 8/31 | XP_011517019.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.1862G>T | p.Arg621Leu | missense_variant | 11/34 | NM_017617.5 | ENSP00000498587 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459624Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 726186
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 16, 2021 | The p.R621L variant (also known as c.1862G>T), located in coding exon 11 of the NOTCH1 gene, results from a G to T substitution at nucleotide position 1862. The arginine at codon 621 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in an aortopathy cohort; however, clinical details were limited (Girdauskas E et al. PLoS One, 2018 Jul;13:e0200205). This amino acid position is well conserved in available vertebrate species; however, leucine is the reference amino acid in other vertebrate species. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at