9-136514525-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_017617.5(NOTCH1):c.2192G>A(p.Arg731Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000252 in 1,586,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. R731W) has been classified as Uncertain significance.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2192G>A | p.Arg731Gln | missense_variant | 13/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.507+4546C>T | intron_variant, non_coding_transcript_variant | ||||
NOTCH1 | XM_011518717.3 | c.1469G>A | p.Arg490Gln | missense_variant | 10/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.2192G>A | p.Arg731Gln | missense_variant | 13/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000393 AC: 8AN: 203782Hom.: 0 AF XY: 0.0000272 AC XY: 3AN XY: 110432
GnomAD4 exome AF: 0.0000209 AC: 30AN: 1434242Hom.: 0 Cov.: 33 AF XY: 0.0000253 AC XY: 18AN XY: 711106
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74362
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2022 | The c.2192G>A (p.R731Q) alteration is located in exon 13 (coding exon 13) of the NOTCH1 gene. This alteration results from a G to A substitution at nucleotide position 2192, causing the arginine (R) at amino acid position 731 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Adams-Oliver syndrome 5 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2022 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at