rs377343669
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_017617.5(NOTCH1):c.2882C>T(p.Thr961Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,192 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2882C>T | p.Thr961Met | missense_variant | Exon 18 of 34 | ENST00000651671.1 | NP_060087.3 | |
NOTCH1 | XM_011518717.3 | c.2159C>T | p.Thr720Met | missense_variant | Exon 15 of 31 | XP_011517019.2 | ||
LOC124902310 | XR_007061864.1 | n.348G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | ||||
LOC124902310 | XR_007061865.1 | n.348G>A | non_coding_transcript_exon_variant | Exon 1 of 3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152270Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000442 AC: 11AN: 248790Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135318
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1460804Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 726714
GnomAD4 genome AF: 0.0000262 AC: 4AN: 152388Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74524
ClinVar
Submissions by phenotype
Adams-Oliver syndrome 5 Uncertain:1Benign:1
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Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.T961M variant (also known as c.2882C>T), located in coding exon 18 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 2882. The threonine at codon 961 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available 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. -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Aortic valve disease 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at