chr9-136509794-T-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_017617.5(NOTCH1):āc.2908A>Gā(p.Thr970Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000577 in 1,612,970 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). Synonymous variant affecting the same amino acid position (i.e. T970T) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.2908A>G | p.Thr970Ala | missense_variant | 18/34 | ENST00000651671.1 | |
LOC124902310 | XR_007061865.1 | n.322T>C | non_coding_transcript_exon_variant | 1/3 | |||
NOTCH1 | XM_011518717.3 | c.2185A>G | p.Thr729Ala | missense_variant | 15/31 | ||
LOC124902310 | XR_007061864.1 | n.322T>C | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.2908A>G | p.Thr970Ala | missense_variant | 18/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000523 AC: 13AN: 248670Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135284
GnomAD4 exome AF: 0.0000582 AC: 85AN: 1460748Hom.: 0 Cov.: 33 AF XY: 0.0000592 AC XY: 43AN XY: 726686
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2023 | Has not been previously reported in association with connective tissue disorders or cardiovascular disorders to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29113320) - |
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Adams-Oliver syndrome 5 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | May 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2023 | The p.T970A variant (also known as c.2908A>G), located in coding exon 18 of the NOTCH1 gene, results from an A to G substitution at nucleotide position 2908. The threonine at codon 970 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Aortic valve disease 1 Uncertain:1
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