9-136499222-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_017617.5(NOTCH1):c.5972G>A(p.Arg1991His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1991C) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.5972G>A | p.Arg1991His | missense_variant | 32/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.5249G>A | p.Arg1750His | missense_variant | 29/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.5972G>A | p.Arg1991His | missense_variant | 32/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152260Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248952Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135200
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460878Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726754
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152260Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74386
ClinVar
Submissions by phenotype
Aortic valve disease 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 19, 2020 | The NOTCH1 c.5972G>A (p.Arg1991His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000165 in the Other population from the Genome Aggregation Database though this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the limited evidence, the p.Arg1991His variant is classified as a variant of uncertain significance for aortic valve disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Adams-Oliver syndrome 5 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at